GABAA Receptor Subtype Involvement in Addictive Behaviour

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Sussex Research Online

GABAA receptor subtype involvement in addictive behaviour

Article (Accepted Version)

Citation: Stephens, D N, King, S L, Lambert, J J, Belelli, D and Duka, T (2016) GABAA receptor subtype involvement in addictive behaviour. Genes, Brain and Behavior. ISSN 1601-1848

This version is available from Sussex Research Online: http://sro.sussex.ac.uk/63064/

This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the URL above for details on accessing the published version.

Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.

Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.

article as doi: 10.1 differences version between lead to this may been through the copyediting, typesetting, pagination andproofreading process, which This article hasbeen accepted for publication andundergone full peer review but has not [email protected] UK BN1 9QG Brighton, Falmer University of Sussex School of Psychology Stephens D N forAddress Correspondence: 678638 1273 +44 Tel GABA DN StephensDN A Receptor Subtype Invo Receptor Subtype 2 Division of Neuroscience, Univ 111 1 School of Psychology, University of Sussex, Brighton, of University Sussex, Psychology, ofSchool / gbb.12321 1 , SL, King

1 , JJ, Lambert Behaviour Behaviour

and and the Versionof Record. Please cite this

ersityDundee, of Dundee, UK 2 , D., Belelli lvement in Addictive Addictive lvement in 2 , and, T Duka UK UK 1 , , Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This encoding GABA sets summ review out brain. to This mammalian GABA Abstract Key Words: Words: Key relevanta across number of differen published literature is on alcoholdependen involvement of GABA to bring togetherevidencefirst attempt from the functioning of brain circuits, control over insubtypes addiction, the partwesummarise GABAA receptor.Inaddition to outlining theevidence for humans, while animal models of addictive be animal impulsivity; model; reward; benzod A receptors form the major class of inhi alcohol; psychostimulant; nucleus accumb A receptor isoforms are associated wi isoforms associated are receptor A Receptor Subtypes in addictive behaviour. While the weig t aspects of addictive behaviour. iazepine; conduct disorder; electrophysiology especially the mesolimbic system, and make a cy, cy, the underlying principles outlined are haviour also implicate certain subtypes of several fields to understanding potential arise the arise evidence that variations in genes icular contributions of these isoforms in of isoforms these in contributions icular bitory neurotransmitter receptors in the ens; gene association; geneens; knockout; gene th aspects of addictive behaviour of th aspects in the involvement of specific ht of the Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This GABA 1.1 GABA 1.1 outlined relevant are across a number of publishedof the literatureonis alcohol depend review concerns itself broadly with GABAergi our understanding of addiction processes, an receptors. GABA additionally includes acetylch central nervous central system (CNS), GABA chloride and bicarbonate ions Si and (Olsen arranged around a central axis to form an circumstances, the electrochemical gradient (combining th complex in an open transiently stabilizes the bindingcells. to spec The GABA, neurotransmitter,the of GABA humananimal providing literature and and behavioural genetic excitability of its target neurons. inhibitorycircumstances, acts neurotransmias an most GABA decreasing the cell input resistance, a “shun acts as GABA susceptible to depolarization byother neurotransmitters such of the in memb a hyperpolarisation resulting This paper outsets to review the evidence for GABA Both human and animal studies have implicated GABA Introduction 1 structure and function of GABA alcoholism and addiction to other drugs of a E Cl , and the cell’s resting membrane potential, V potential, membrane and, the cell’s resting A A receptors are members receptors are of the receptors in receptors addictivebehaviour. weFinally, A receptors receptors A receptors are heteromeric protein comp A oline nicotinic, 5HT3, and strychnine-sensitive glycine receptors and their before diversity, subtype reviewi A receptors expressed are in both neurons and glial cys different aspects of addictive behaviour. -loop familyof ligand thatgated ion channels eghart, 2008, Macpherson et al., 2016). In the 2016). In the Macpherson al., et 2008, eghart, c systems and addictive behaviour, the weight systemsc weight andaddictivebehaviour, the d their underlying neurobiology. the While ency. the underlying Nevertheless, principles anion-selective ion channel, to permeable buse. It will begin with a summary of the of the buse. withIt will a summary begin rane that, inthat, rane turn, makes neuronthe less conformation, allowing ionic flux. In most will attempt to integrate these data into data these into integrate will to attempt m ) allows for an influx of chloride ions for an influx of chloride ) allows A receptor involvement in relation to A receptors in receptors addiction processes. ific bindingoncomplex, sites the lexes, composed of five subunits five composedlexes, of t” for incoming signals.t” for incoming in Thus, e reversal potential reversal e forCl as glutamate.by Moreover, tter, dampening down the evidence for evidence therole of ng the - ions, ions,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This of structurally diverse of diverse structurally including 1), the benzodiazepines, certain receptors also possess avariety of allosteric si subunit interface. In mammals, differe nineteen interface and that for benzodiazepines in The GABA Moss, 2003). (Kittler and binding site is locate incorporate kinase consensus sequences that ion por to the which contribute loop may betweenTM3 and TM4 of which TM2 (TM1-4), is thought to line the benzodiazepines interact with complex) the domain (at which extracellular that pore forms the ion channel (Fig 1). Each subunit cons GABA bindingIn addition to expressing sites multiple members: members: multiple onand se classified into eight based families, inhibitors, picrotoxin acts as a GABA as inhibitors, picrotoxin acts

for Zn and(NAM) as the latter a true competitive anta with the form forGABA, the bindingto, site close of the forming the lining chloride ion channe 1.2 Subtypes of GABA Subtypes 1.2 alcohol. GABA-enhancing action,neurosteroids the and of concentrati the agonist.presence Additionally, at greater enhance the stabilising function of GABA by the open conf compounds as act and Lambert,2005). These that benzodiazepines do not this share receptor-channel complex in of the absence GABA A 2+ receptors typically are composed of 5 , which may act as an endogenous modulatorGABA an endogenous of as act may which , α (1–6), (1–6), A i.v. receptor receptor general anaesthetics general β (1–3), both the the naturaland pharmaceuticals ligand,GABA, both such as A receptor antagonist, receptor by bindingamino acid residues to (1–3), (1–3), property.“agonist” GABA regards As for GABA, for GABA, the natural naturally occurring neurosteroids and a number an equivalent location between the quence homology. Several of the families have , four hydrophobic transmembrane domains domains transmembrane four hydrophobic , tes at whichnumber a of agentsother act (Fig pore ofpore the channel, andintracellular a large e.g. l pore. Bicuculline and gabazine bind or to, and gabazine pore. Bicuculline l protein subunits arranged around a central influence functionreceptor and trafficking , , gonist. Additionally,gonist. binding are there sites er acting as a negative allosteric modulator a negative as acting er nt subunit proteins have been identified, positive allosteric modulators (PAMs) to ε , a so, called “GABA-mimetic” Note effect. propofol, etomidate, barbiturates (Belellietomidate, barbiturates propofol, , , i.v. (1–3), anaesthetics can directly the gate anaesthetics d between d between the ons than those required for this ons ormation of the channel in the of the channel in the ormation θ and A R function,R for and possibly ists of N-terminal a large neurotransmitter, GABAneurotransmitter, e pathwayalso may ande , , and within a family, α and A β receptor receptor α subunit and γ A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This conductance, ion channel kineti Different combinations of subunitsdiffering have physio Fig here near 1 distributedwithin and within neuronal cellular brain, the Most mammalian appearreceptors to consist of 2 of members chromosomal localisation, for co-ord als (see 2014); Panzanelli, and Fritschy 2009, Sieghart, of40) GABA pentameric re in (over a a but structure million), give possibilitthe fosters subunits diversityof This the protein (Bat product GABA subunits have a high sequence similarity (Ols recently significant is interest made up of (Walker(PAMs) and Semyanov, distinct 2008). A group of bind to bind modulatorsallosteric (NAMS) (i.e., they reduce t fashion andchannel are an allosteric the in and members of the isoform, hybrid receptors wi receptors isoform, hybrid an complex, it must contain particular members of the members particular must complex,contain it complexes. for Thus, classical benzodiazepines ( GABA, someallosteric modulators interact wi for Furthermore, co all although the natural ligand 1998). subunit(Fig 1). Alternatively, in less abundantsubtypes, β subunit. While for any individual both receptor, A -carbolines act at these benzodiazepine-sen these at act -carbolines subunit isoforms (e.g. subunit isoforms α 4 and4 A receptor subtypes estimatebeen have receptor α 6/ β family, and a and a family, β/γ 2 complexes where they function as positive alloste eson et al., 1991, Pe al., 1991, eson et th two different forms of 2, 2, cs) and pharmacological properties and heterogeneousl are α 4 &4 γ 2 2 However, subunit. certain atypical benzodiazepines inated expression of subunits).inated expressionof α 6), alternative splicing allows a further complexity in in complexity further a splicing allows alternative 6), α 4 or 4 trie et al., 2001). 2001). al., et trie y y number large for a very of to permutations th only a subset of possible these th only a subset receptor hus termed agonists”“inverse or hus negative α en and Sieghart, 2008). Further, for some 2008). Further, en and for some Sieghart, the effects ofGABA). the substancesThese also e.g. 6 subunits6 with together sitive sitive complexes to negatively modulate diazepam) receptor to withinteract the d to be naturallyto be expressed (Olsend and ality, only a limited number (about only30- a ality, α o Section 1.3, GABA 1.3, o Section α subunits likely are same to be of the α family ( the subunit also occur (Nusser et al., mbinations known to exist is knownis to exist mbinations receptors that receptors has received subunit is replaced by a logical ( the α domains. receptors Thus, 1, 1,

α α 2, 2, family, 2 family, e.g. α A 3, 3, β receptor subunit single channel single and α ric modulators 5) along with with along 5) β δ , and one and, subunits. or y y γ

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This respectively, while an action at the the well-characterised amnesticbenzod of effects mediated by mediated the sedative properties the sedative and anxi of administration the with associated normally repertoire Behavioural analysis of these mouse lines has incorporating the mutated subunits (Rudol α number ofmouse lines toengineered a mutated harbour of this observation, the groupsadvantage led by and Möhler histidine (H) in the homologous position of the benzodi from the other family members by virtue of a Alternatively, up made of receptors members of the containing extrasynaptic cellular domainscellular ( extrasynaptic However, al., 2012). et Fritschy 2005, Nusser, cluste to gephyrin), as (such proteins scaffold region-selective distribution of subunits the various sug Walker 2013, al., et Herd et 2009, synapse (Belelli al., exclusivelyan extrasynaptic localizationrespond to and may which individual ofmembers the This proposal found substantial support from a 2003). Whiting, 1996, Whiting, classical benzodiazepines ( heterogeneity likely subserves differential func wide variety of GABA of wide variety actions ( subtle behavioural than effects those typically displayed by combination of targeting a particular subunit pharmacological 2(H101R), 2(H101R), e.g. α α classical benzodiazepines andbarbiturat 1, 2, 3 or 3 2, 1, subunits, 5 together with 3(H126R) or 3(H126R) α 1-containing α subunit family, the benzodiazepine-insensitive A receptors receptors located within different neuronal networks (Mc α e.g. 5(H105R) to impart benzodiazepine

diazepam). sequence Despite their high homologywith othe and e.g α olytic properties of benzodiazepines have beenhave shown olytic properties of to benzodiazepines 5-containing receptors makesa significant contribution to . α α α α4 5 2- (and perhaps (and 2- family were mutated to render them insensitive them to render mutated towere family β or 2 receptor subtype (Fritschy and Panzanelli, 2014)). 2014)). Panzanelli, and subtype (Fritschy receptor 2 α6, r r at the postsynaptic membrane(Farrant and allowed the dissection of the pharmacological ph et al., 1999, McKernan et al., 2000). ph et 2000). al.,et al., McKernan 1999, inwith combination crucial arginine (R) re β1/ tional and so that the physiological roles, the same isoforms can also localise to localise the isoforms can also same iazepines (Mohler et al., 2002, Collinson et et Collinson (Mohler al., et 2002, iazepines series of elegant experiments in mice in in experiments ofseries elegant mice 2/3 and and 2/3 es), es), at which a transmission facilitate gested on early that GABA α and Semyanov, 2008). The brain and 2008). Semyanov, 3-) subunit containing receptors subunit containing receptors 3-) classical benzodiazepines. Thus, Thus, benzodiazepines. classical azepine binding domain. Taking drugs with a broad spectrum of γ α 2 subunits2 interact withlargely subunit gene gene subunit insensitivity to the receptors overflow of GABA from the may associate with more with more associate may α McKernan developed a 4 and and 4 β and sidue, which replaces α δ 6 subunits differ subunits 6 subunits exhibitsubunits i.e.

Kernan and and Kernan α A 1(H101R), 1(H101R), receptor be r r Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This data point to quite for subtypes separate roles of GABA for benzodiazepine-like targets potential selective an ligands Althou al., et 2013). Kretschmannova 2003b, al., In humans, genes encoding 14 of the 19 GABA 19 the of 14 encoding genes humans, In of distinct of distinct a similaretomidate, approach has been also associated anaesthetic with ( usage general al., 2006, Rudolph and Knoflach, 2011). Taking advantage o advantage Taking 2011). Knoflach, Rudolph and 2006, al., 1.3 GABA 1.3 and hencefunction. behavioural these genes. Thus, cluster 4 ofthe chr GABA human clusters occur in the mouse2) su (Fig clusters located on chromosomes 4, 5, 15 and X (F X and 15 5, 4, on chromosomes clusters located α cluster (chr 5) contains genes for chromosomal cluster may be co-regulated ( raisesin genes asclusters to question the 1997). al., et (Garrett (chr11) 11 chromosome chromosomes ( correlation expression of gene between GABAergic genes (Laurie et al., 1992, Pirker Schwarzer et 2000, al (Laurieet et 1992, al., al., cluster (chrencoding genes 4) contains Wilco al., et 1990, Sommer Russek1992, Farb, 1994, and et Greger 1989, al., et Bell al., 1995, et McLean the where VTA, they continue (especially the hippocampus, amygdala, the majority of dopamine (DA) neu mammals, structures in except particular 1992, al., et (Wisden rat adult the inregulated 4 (and mouse 8)chr predominate in rodent embryo, but the chromosomewww.ensembl.org), (chr 8 8; and the human c 5, 5, β 3, 3, γ 3 subunits andX chromosome 3 the A Receptor Subunit Chromosomal Localisation Localisation Chromosomal Receptor Subunit β subunit-containing isoforms ( trans effects). Interestingly, expression of those genes l α 1, 1, α 6, 6, γ β β 1, 1, e.g. 1-3) to the constellation of behavioural1-3) effects 2 and2 cis α whether the expression of genes within each successfully applied to α 3, 3, theincluding thalamus, cortical areas, sedation, immobility, hypnosis) (Reynolds et ggestinga highly conserved organisationof 2, 2, and,effects) additionally,whether there is A Laurie et al., 1992), and presumably other other and presumably Laurie al.,et 1992), al., 1995, Hicks et al., 1994, Johnson et al., al., et Johnson 1994, al., Hicks et 1995, al., A receptor subunits receptor are found four major in α ε genesreceptor also is found on mouse The highly conserved gh acquired in the context of discovering gh acquired in the discovering context of 4 and and 4 , and, ig 2 (Buckle et al., 1989, Dean et al., 1991, 1991, al., et Dean al., 1989, et (Buckle 2 ig α γ 4 and4 2 subunits,2 the ., 2001). ., A θ receptor in receptor different brain circuits, α x et al., 1992). The chromosome 4 4 The chromosome 1992). al., x et subunits. Syntenic regions for the 2 to genes) be expressed highly β 1 subunits,1 the chromosome 5 rons in therons substantia nigra and that are located that in different d general anaesthetics, these f the se se are genes generally down hr 5 cluster 5 onhr mouse

chromosome cluster 15 dissect the contribution β -subunit of selectivity ocated on human chr organisation of the organisation Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This 2.1.1.1 GABRA 2 GABRA 2.1.1.1 It is noteworthy that three of clus 5 the chr noteworthy that three It is 1 In the remainder of this reviewdi Inof the remainder this shall we 2.1.1 Chromosome 4 cluster: ( cluster: 4 Chromosome 2.1.1 studies gene association Human 2.1 modestly (0.7–0.6). second A grou factor, whilefactor, the chr 4 gene GABRA4 ( genes, GABRB3 (encoding subunit were highly, correlated notonly genes 5 with other gen Enoch andcolleagues (Enoch al.,et 2013) suggested that the coordinated transcription (Enochwithin clusters encompassing ventral tegmental area (VTA) and studies implicatingstudies an for GABA important role both both e.g be the main narrative of this with additifocus because of its widespread abuse and availabilit GABA α2β1γ1 particular receptor assemblies. assemblies. receptor particular mechanism underlies coordinated expression (Enoch et al., 2013). Such correlations of ex GABRA4 expressionnote that authors correlate gene expression: GABRG1 (1.0);GABRA2 (0.8); GABRB1 cluster,chrloaded 4 onto that account a factor

. cocaine and amphetamine-likepsychostimulants where appro Evidence for GABA cis A

α that is found inalmost th exclusively and 1 β 2 γ trans 2 receptor, while receptor,2 the 4 chr genes encodethe GABA correlations of gene expression. In pa correlations expression. of gene A receptor involvement in in addiction involvement receptor γ1, α p of genes, namely the four GABA β 2, α4 3) and( GABRG3 α and 4) and the chr X ( GABRA3 gene ter genes encode ter genes the most frequently expressed scuss from bothhumanevidence scuss and animal pression levels might suggest that a common β1 onal references to other substances of abuse substancesother of to references onal ed for 0.14 of the total variance in GABAergic the totalof variance ed for 0.14 y of considerable documented ofy considerable willresearch, d better with expression of the chr 5 genes with better expression genes 5 d of the chr ) ) of some favouringsubunits, formation of e addiction-related mesolimbic pathways addiction-relatede mesolimbic pathways et al., 2013). A recent factor analysis byfactor recent A al.,et 2013). A ventral striatal regions, consistent with receptors in drug addiction. Alcohol Alcohol addiction. drug in receptors γ 3) also had high3) also loadings(0.8) on this es within that cluster,but two withines that 15 chr (0.8) and GABRA4 (0.5), though the rticular, expression levels ofrticular, expression the chr GABA priately documented. A receptor subunit group A A subunit genes in the gene clusters show clusters gene α 3) loaded more

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This While several studies havelink between confirmed a GAB alcoor drug, to rise disorder gives might su Such evidence 2014). al., et (Melroy withboth (rs9291283) SNP particular only a dependence in alcohol this population 200 al., (Dick et associatedwith symptoms conduc of childhood drugs (Agrawal al.,et 2006), while a further study association held only for those alcoholics whoa analys subsequent However, 2008). al., et (Soyka dependence(Edenberg al., et 2004). This GABRA2, morewith the commonhaplotype be cohort) have identified two haplotype blocks recentMore (using studies the Collaborative Study on the Ge al et et Reich al., Porjesz 2002, al.,et 1998, Long 2003, dependence and chromosomethelocation 4p at of the GABA numberA of studies over the past twenty has years sugge to with alcoholics comorbid illic to In contrast (FehrGermans al., et 2006). and origin (Covaultet of Caucasian in Americans et al., 2004), was shown was 2004), trai to al., possesset a high which an suggested association of the more fr with keeping (Enoch al., et th that interpretation, 2006). In however, possession of trait anxiety by itself haplotype (Enoch, (See 2008) also discussion below o whileanxiety, low-anxiety be may likelymore alcoholics more frequent haplotype being associated wi These apparent paradoxes may reflect differen relationship to be most prominent in individua studies have found that frequent the less hapl it drug dependence, others (Covault dependence,al., found 2004) drug th others it et hol misuse as partthe of disorder. findingwas confirmed in population a German alcohol abuse and alcohol wasconduct disorder found al., 2004), Russians (Lappalainen et al., 2005), 2005), al., et (Lappalainen Russians 2004), al., t anxiety compared to the non-alcoholic group to the group non-alcoholic compared t anxiety was not associated with GABRA2 variations variations GABRA2 with not associated was equent haplotype with alcoholism (Edenberg extending downstream from intron 3 within from intron within 3 downstream extending otype otype is associated with alcohol dependence the Agrawal report that limits the association the limits that report the Agrawal ls without comorbid illicit drug dependence. comorbid drug without illicit ls dditionally had dependence on other, illicit, t populations of alcoholics, those with the populations of alcoholics,t those withthe th alcoholism characterised by high trait ggest that geneticall ggest discovered that the GABRA2 that were variants discovered is of the COGA dataset revealed of thatthe COGArevealed this is dataset t disorder in children, though not with ing a significantforalcoholrisk factor 6b). More recently, an association of ., Zinn-Justin1998, ., 1999). Abel, and n Type I and II alcoholism);Type RA2 variants and alcoholism, other RA2 sted a linkage between alcohol topossesslow-frequency the e COGA alcoholic population alcoholic COGA e population netics of Alcoholism (COGA) A gene cluster (Ghosh gene al., et

y-associated conduct e e Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This A recent meta-analysis found meta-analysis recent A associat strong Although a number failed studies have of that finds GWAS only weakassociatio disorders of behavioural control associated withva GABRA2 evidenceDisorder”phenotype, and the as a thatalcohol abu alcoholism be minor. may However, genetics that the contindicating perhaps 2010), direct Disorder, wi with Alcoholassociation Use (p<0.05) controls, GABRAfive 2,000 alcoholics and 2,000 nearly GWAS failed have studies to thesupport wide al., (Li et Disorder Use Alcohol and rs3219151 associ significant A and heroin rs211014. for and GABRG2 between and and rs279858), rs567926 for SNP onset alcohol abuse and aggression). onset alcohol and abuse aggression). infrequently seen more Cloninger alcoII Type dependen alcohol and rs279858 not alcoholand dependence, rs9291283) only showe and whichal., 2015), examined associations is strongly he exclusivelyalmost in seen males, herita is not I Whereas strongly Type 1988). al., alcoholism and pr onset, with early a relatively characterised by late onset and neurotic predisposition, and pointclassification of view,of alcohol use the while do females not in show males, strongest heterogeneity of oftypes alcoholism, this may not be sur Ma al., et 2006, Drgon al., 2008, (Covault et alcoholism resulted fromterm long alcohol thanrather abuse being a it be dete in this case cannot though, 1995), subunit in the mRNA central amygdala nucleus (Ducci al., et Importantly, mort 2007). a post ce, but the A–C (rs567926 and rs279858) haplotype was was haplotype but the andce, rs279858) (rs567926 A–C ns of GABRA2nswith alcohol abuse. between three GABRA2 three rs279858 between (rs567926, SNPs em studyofof em brains alcoholics found lower ions between GABRA2 andalcoholdependence tofind an association between and GABRA2 rmined whether the lowe 2014). Nevertheless, and perhaps surprisingly, and perhaps surprisingly, 2014). Nevertheless, holics (presenting with a combination of early such an association (Enoch, 2008). From this such an From this association (Enoch, 2008). esence of delinquent behaviour (Cloninger et ble and found more often in females, Type II, II, Type in females, found often more ble and ation was also observed between GABRA6 between observed also ation was ly replicated GABRA2 finding. In of a GWAS disorders is of interest. Type I alcoholism is I alcoholism is is of interest.disorders Type given the given heterogeneityof “Alcohol Use ritable. In keeping,recent study a (Strac et ribution of GABRA2 genotypic variants to variants genotypic GABRA2 of ribution of alcoholic patients (Cammarota al., et th odds ratios of 1.1 – 1.7 (Bierut et al., al., et (Bierut – 1.7 1.1 of odds ratios th predisposing influence. tthews et al., 2007), given the the given tthews al., et 2007), prising. The associationprising. may be riants, perhapsit is unsurprising 2 SNPs had only a nominal only a nominal had SNPs 2 dependence both on alcohol on dependence alcohol both se is only one of a number of number a is only one of se distinguished from Type II d an association between dbetween an association red expression level level expression red α 2 2 Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This There is only from limited evidence association gene st Some studies have reported have robustSome studies a association between 2.1.1.2 Other chromosome 4 cluster GABA 4 chromosome Other 2.1.1.2 population (Odds RatioCo 4.2 [95% rs2044081 in rs2044081 has been recently, Very association an 2005). Fo and Dick Zhang, 1999, and is (Parsian less clear the associationof although the al.,et 2011), strength Kertes comorbidwith substanceother dependence and psychiatric African descent (Covault et al., 2008). Note th 2008). Note (Covault al., et African descent identifiedof Am in two groups intron was 3 block from the intergenic that extends bloc for two G trend for association study a reported al., 2004) subunit locatedgenes on 4pchr may be involved in addi abuse provide independent contributions to alco provideto independent contributions Nevertheless, other researchers reported that the GABRA2 markers in the GABRA2 contribute to risk of alcohol dependence in inare linkage disequilibriumwith on markers the GABRA2 the BOLD response found in the right hemisphere supramarright foundin the response theBOLD performance was higher in the minor (T) allele group. hemisphere caudate/insula, and left hemisp However, increased BOLD response in the righthemisph of impulsivity, or a monetary incentive dela a performancealtered with inassociate either in dr implicated are that reward sensitivity and associated with perfor SNP is of this variant et we 2010), al., explored anin adolescent (M.Y.Morgan alet (personal communication). GABRB1 and alcohol dependence in British/Iria well characterized

gene providinggene the dominant effect (Covault al., et 2008). nfidence Intervals 1.5-11.5] P Intervals 1.5-11.5] nfidence hol vulnerability (Enoch et al., 2009). hol 2009). vulnerability(Enoch al., et mance of tasks measuringaspects of impulsivity, k between GABRA2 GABRA2 GABRG1 between k andto up GABRG1 population whether possession of the minor (T) (T) population minor possessionwhether of the A ericans of Caucasian origin, of but not those at the polygenic marker y (MID) task y(MID) assessing anticipation. reward receptor subunit association with alcohol receptor with subunit association ug and alcoholabuse. Allelic variation did not Exploiting the database IMAGEN (Schumann an additive manner, with the polymorphic stop-signal taskstop-signal one (SST), measuring aspect here inferiorhere temporal gyrus during MID the intergenic identified between SNP roud, 2003, Song et al., 2003, Reck et al., al., et Reck 2003, al., et Song 2003, roud, In during contrast, SST performance, ction risk. The original (Edenberg et udiesother that GABA GABRB1 ABRG1 SNPs, while a haplotype while a haplotype SNPs, ABRG1 gene, and foundbeen have to with alcohol dependence alone dependence alone with alcohol ere inferiorere frontal gyrus, left ginalright hemisphere gyrus, illnesses (Yang al., et 2012,

and GABRG1 and alcohol dependence s in the GABRG1 gene gene GABRG1 in the s corrected

anxiety, hostility and depression scores, but not with alc and but depression hostility anxiety, scores, the same allele was associated with lower leve alcohol, and each had developed alcoholism du (Pro385/ withmen heterozygous and who individuals were only 18 heterozygous a uncommon, is allele Ser385 The 2005). al., the alcohol and dependence, non-significant a for anasso trend alcohol is thou following of sedation lowA level dependence in a German population. of no association found 1999) al., et study (Sander antisocial alcoholism with (Loh (Loh while al.,et Scottish al.,et 20 study 2000b), (Radel et al., and 2005), with both alcohol dependence and associated with alcohol dependence in both 2006c). alcohol (Dick al., et includedhistory of blackouts, at these age a found an associationof (Dick and Song al.,et 2005, alcoholism 5 genes addictions. Initial analysis of data the COGA There is considerablyless thatevidence withingenes th cluster 5 Chromosome 2.1.2 GABA 1999), (Iwata al., et children of alcoholics substituti same the Curiously,

genotype. We suggest suggest thatWe genotype. lingual and left hemisphere infe susceptibility to addictivebehaviour (Dukaet al., in pr important brain regions inreward-re controlling GABRA6 A receptors incorporating the Ser385 allele and a low sedativeand a lowresponallele Ser385 GABRA1 GABRG2 Other membersOther of the cluster, ( β α 1-containing GABA 1, 1, on is associated with reduced tosensitivity in diazepam rior parietal gyrus indicated reduced responses in the in responses reduced indicated gyrus parietal rior with individual indications of risk for alcohol depe alcohol for risk of indications individual with α Ser385) genotypes had the lowe genotypes Ser385) 6, 6, in a Japanese population. Ontheother hand, another α β 6 subunit. Perhaps Perhaps subunit. 6 a the substitutionsub- induces 2 and2 base revealed no linkage between chromosome though classic benzodiazepinesdonot bind to γ nd the study contained no homozygous cases, cases, homozygous the study contained no nd 2) a Finnish, and a Native Americana Finnish,Native anda population first and level to drunkenness, response of lsand of neuroticismconspicuously,reduced ring follow-up. ring previous in a However, study, ght to represent a risk factor for developing factor a forrisk developing ght to represent for the Ser385 allele. Nevertheless, the six Nevertheless, for Ser385 allele. the et al., 2003), though a al.,subsequent et 2003), analysis A lated behaviour, which may contribute to to which may contribute behaviour, lated receptors may play a role inexcitability of play a role receptors may se tose alcohol has been reported (Hu et ess). GABRB2 e e chr cluster 5 areassociated with

00a) of reported 00a) association an G ABRA6 andABRA6 ciation possession of between ohol use (Sen et al., 2004). ohol use (Sen et 2004). al.,

, or, Korsakoff's psychosis in a st sedative response to response to st sedative GABRG2 GABRB2 with alcohol with ,

have been ndence; ndence; minor minor Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This chromosome X ( 2.1.4 actions. fortarget Ro 15-4513 of the relevance question et 2011) al., (Linden is binding Ro 15-4513 that moreover, toinsensitive this atypical BZ ligand by a point mutation in bindi 90%Ro 15-4513 approximately affinity of high et Rewal reward 2009, alcohol (Rewal al., et high target affinity that Note al., et 2012). (Lingford-Hughes alcoholicpatients, particularlyin limbic regi α exploit [ 2010) al., et and Luddens, Wieland Momosaki 1994, incorporating for the higher affinity benzodiazepine Ro15-4 derivative, The atypical imprintinggenetic (Meguro al.,et 1997). with consistent 2003), al.,et (Song alcoholism maternal, transmissionnot of between alcohol dependence and Studies using the COGA dataset have found evidence of ha cluster ( 15 Chromosome 2.1.3 sedation. phenotype a arousal, threshold in increase disorders in human populations. unaware are of any studiesWe indicating asso 5-GABA 11 A C]Ro15-4513 binding in PET studies of human brain as a me a of human brain as studies in PET binding C]Ro15-4513 Rs. Using this method, Using Rs. of the expression α1, α2, α3 α4βδ α 3, 3, α subunits, both for both subunits, for receptors (Hanchar al., et receptors 2006) 5 subunit-containing5 GABA ε , and, α

5, 5, θ GABRA5 ). β GABRG3 3, 3, prominent in regions devoid of prominent in regions γ 3) 3) and in vitro Ro 15-4513 had been suggested previously to to previously been suggested had Ro 15-4513 (Dick et al., 2004). Interestingly, paternal, but paternal, but Interestingly, 2004). al., (Dick et ons, including the nucleusaccumbens (NAcc) that could independent reduce that influences on the However, al.,demonstration 2012). that this chromosomal location being subjected to being location chromosomal this GABRB3 ciations of these genes with alcohol-related 513, has been reported to have a relatively a relatively have to reported been has 513, and -GABA α ng is lost in the brains of mice rendered , and this observation has been used to to been observation has used and, this A 5-GABA receptors ( alleles showed associationalleles showed with in vivo in A receptors as a pharmacological receptors as , which have been implicated in implicated been which, have A Rs is reduced inRs the brains of studies (Luddens al.,et 1994, plotype and SNP association the the α 5-GABA asure of the density of of density the ofasure 2 2 subunit (F77I), and, subunit expression A Rs) over those over Rs) Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

While by on gene-a the majority far of studies Subsequent suggestedhave studies associations of GABA 2.1.5 alcohol dependence, a limited investigatednumber have the subunit genes and addiction abused to other exposure to severe childhood trauma. A fu A trauma. childhood exposure to severe more common in control subjects and seemed al.,et 2010). heroin One haplotype predicted heroin and cocaine, alcohol, of diagnoses comorbid gene. 2014). Finally, a gender selective association of the no the association of selective Finally, a gender 2014). increases expression of association did not survive stri withopiate or cocaine dependencewas repo Chinese people. Veryrecently, further evidence for an al., et and 2014), (Chen 2016). Cadet, 2008, al., et Messina(Enoch, 2011, a factor know stress, to early-life vulnerability drugs, particularly to cocaine. vulnerability, addiction i Thus, with addiction; inte heroin childhood trauma in implicated block and potentially haplotype receptors containing the the containing receptors regulates mRNAregulates transcription and thusstability and may ex alter thehaplotype. same This and other intronic reportedwidely with disequilibrium rs279858 frequently for the alcohol studies, one riskSN a differen characterised our study While 2010). with cocaineBrazilian addiction in povariants a 2008b) and cannabis abuse (Agrawal et et al., cannabisand abuse 2008b) (Agrawal

In a parallel study, African American male GABRA2 A receptor other with associations addictions variants may contribute to the deve variants contribute may GABRB3 α2 GABRG2 subunit playmay a role in nicotine dependence (Agrawal e ngent analysis. Reporter gene assays find the risk al risk the find assays gene Reporter analysis. ngent and this and may contribute to its pathogenesis (Chen et al., (Loh et al., 2007) SNPs with opiate dependence in Han in withal., SNPs et 2007) Han opiate dependence (Loh 2008a). We found an association found We an association of 2008a). drugs. Human genetic studies suggest GABAdrugs. studies genetic Human suggest racted with rs11503014 variation to influence variation withracted rs11503014 P from our study, rs279871, is in 100% linkage linkage 100% is in our study, rs279871, from P rther SNP, rs11503014, not located in any not located in any SNP,rther rs11503014, n to predisposeadultn addictive to behaviour addiction, whereas by other groups, suggesting we are studying are we suggesting by groups, other exon splicing, was independently associated SNPs in a the SNPs regionvicinity may tag that ddiction associations have concentrated on pulation of Caucasian ancestrypulation of (Dixon et al., t set of SNPs from those reported most reported those of from SNPs t set rted though al., et (Levran 2016), this patients with lifetime DSM-IV single and to confer resilience to addiction after dependence were characterised (Enoch (Enoch characterised were dependence GABRB2 vel SNPs rs2279020 and rs4480617 in in and rs4480617 rs2279020 SNPs vel lopment of addictions by increasing association of n some and for populations, some association of GABA (Kim et al., 2015), GABRB3 GABRB3 2015), al., et (Kim pression of the a was a second haplotype GABRB2 and A receptor receptor GABRA2 GABRA2 GABRB3 t al., lele lele A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This 2.2.1 Altered2.2.1 expression of GABAergic genes Several rat linesSeveral been have rat bred forhigh alcohol consum In the accompanying sectionsboth st of types 2.2 Animal studies implicating GABA implicating studies Animal 2.2 The human linking GABA association studies gene exposure.However, surprisingly fewstudies soug have receptorexpression in discretebrain bo areas, parallels to human high consumption, and allowdirect measu taking taking alcohol but extended to drugsother with abus consumption. tosuch alcohol, studies as can obtain di for alcohol-related behaviour. More sophistic experimentsthey provide much of the data into the underlying mechanisms. However, becaus modelhumanconsumptmeasure that to appears selectively bred for high alcohol intake and ge receptors in drug abuse. Drug ( Drug abuse. drug in receptors abuse and dependence, paralleled are by functional studies 2003). 2003). the consumption, and their non-preferring counterp independe lines of rat pairs 5 among differences gene 2013b al., et McBride 2012, al., et (McBride receptor expression gene invarious alcohol pref GABRA1 and GABRG2 with methamphetaminewith been have abuse reported (Lin al. et e.g. A alcohol) consumption investigated bothin animals receptor in subtypes drug abuse scriminate motivational and between effects ) are notable common) are a paucity of in showing on the consequences of genetic manipulation manipulation of genetic consequences onthe e e and dependence liabilityas appropriate. ated measures include operant performance udies will be reviewed withan emphasis on thin drug-naïve animals, drug and following erring lines. Studies from the Indiana group group Indiana the from Studies lines. erring neticallydirect altered provides a rodents, arts, in brain areas commonly implicated in commonly in brain implicated areas arts, in animals selectively bred for high drug high bred for selectively animals in e ofe the relative ease of performing such A ion, but provides relatively insight provideslittle relatively but ion, receptor subtypes to subtypes receptor drug and alcohol ht to identifyin changes GABA ption. These lines provideption. lines These certain in animals these investigating ntly bred for high alcohol alcohol high for bred ntly rements to be ofmade A

2.2.2 Gene association studies: Gene2.2.2 association (Stankiewicz al.,et 2015). hippocampus non-preferring rats, without exposure of Gabrg3 also a significant in exp up-regulation show addicts). rats P contrast (in to the their inregulated rats P protein, required gephryin, for postsynaptic clusteri Gabrg2, Nevertheless, some studies using microarrays to investig

genes (at inleast the brain areas studied). does not depend importantly upon varying expression lev consumption, and, fromview of the point of different combinations of which selected are during sele thathigh alcohol consumption suggest findings area. None None area. of these differences involved genes encodin GABA function,GABA so that may the iP rat a compensatory produce iP primary; hasrat a lowerthe GAD expre ventral pallidum (Halyburton al., et 2007). also exhibited significantly higher levels of the subunit in thewashippocampus higher of the iP preferring) than (non-preferring) iNP level and the rats encoding the gene expression reportedhave altered GABA addictive behaviour, Gabrb3 A receptor. with expression, gene together encoding the independent In an 2012). al., (Enoch et β 1 1 of the GABA subunit e.g., γ 2 subunit, together with subunit, 2 together the accumbens shell, central amygdala and ventral tegmental

Drug self-administration to alcohol, a down-regulation of down-regulation to alcohol, a A high was 1.6-fold receptor down in regulation human and cocaine alcoholics ssion in the hippocampus, suggesting reduced

These differences in expression may not be the current review, such selective breedingsuch selective the current review, A α gene expression. Thus, the of level mRNA is under the control of many diverse genes, diverse under many thecontrolis of a trend trend towardsa a down-regulation 1 subunit1 relative protein in rats to the NP than iNP rats (Homer et al., 2007). P rats rats P (Homer al.,et 2007). than rats iNP Gphn line of Warsaw alcohol-preferring and alcohol-preferring of Warsaw line ng of GABA encoding the associated scaffolding of expression theforof mRNA

g g GABA ate ate differencesgenome-wide in ctive breeding for ctive high alcohol els of GABA of els A A receptors, are are receptors, both up- receptor subunits. Such subunits. receptor er iner iP (Indianaalcohol ression of Gabra4 upregulation of the A receptor receptor subunit was found in Gabrg2 and α 1 1

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This The availability of extensive number of mo an suchstudiesnot have suggested an involvement of chrom partlyalready compromised by altered level of allowing alcohol (or any other agent) to exert genes in the level of performance of the respec of these subunits in the effects of alcohol, or whether associatio these whether not it clear is Nevertheless, γ found only for forebrain expressionfound levels only for forebrain of the 2002, Phillips et al., 1996). Using the Using WebQTL al., et 1996). Phillips 2002, 1998, and Cunningham, Risinger 1994, al., et alcohol-inducedaversion, hypothermia, and al or overlapping loci are associatedalso with encode GABA alcohol dependence have identifiedbeen in consequencesof alcohol administration, or usuallyare based on simple measures of alcohol consumpti mouse and human studies (Ehlersal., 2010). et The availabilityofal., approach2002). related gene expression of the respective GABA the respective of expression gene al.related (2004) et Boehm al., et 2003), Chesler and of alcohol- aspects several (QTLs) of associatedgenes with complex beha mice BXD strains)(so-called has been exploitefrequently from F novel the inbreeding inbred strains genes encoding alcohol-related phenotypes were found for mouse chromo an extent depending on the behaviour, and brai forebrain; significant correlationsfound were encoding withdrawal regionalcoholmous spans a on 3) with significant correl α 1, 1, A A α 6, 6, receptor subunitsreceptor (Boehm(see al., et α 2, 2, β 2 and and 2 α 6, 6, β ation with expressionation with of 2 and and 2 γ 2 subunits (Buck et al., 1997, Bergeson et al., 2003), 2003), al., et Bergeson 1997, al., (Buck et subunits 2 other drug-related behaviours (Crabbe et al., 1999, Phil 1999, al., et behaviours (Crabbe drug-related other γ 1 subunits,1 and in cases these significant correlations we 2 A C57BL/6Jcross between receptor subunits in either cerebellum or chromosomalregions that contain that genes alcohol tolerance, alcohol-conditioned taste its effects readily more when performance is (www.webqtl.org) facility (Wang et al., 2003, al.,et 2003, (www.webqtl.org) facility (Wang for individual butsubunits, these differed to cohol-induced motor incoordination (Crabbe e chromosomee that 11 contain the genes es ines humans offers the hope of integrating Browman and Crabbe, 2000, Kirstein et et and al., Browman 2000, Crabbe, Kirstein withdrawal, several associated QTLs with use recombinant inbred strainsderivedby gene expression. gene Onexpression. hand, the other that While, for practical reasons, such analyses such analyses reasons, practical for While, n area studied.Similarly, associations with α these behavioural observ behavioural these tive tasks used to assess alcohol’s effects, used tasks tive to assess vioural traits includingto responsiveness β 2 subunit:2 for chromosome ( 7 3, and chromosome 4 ( 4 chromosome and 3, ns inform on a functional involvement involvement on a functional inform ns 2004) for a review). Thus, a QTL for Thus,for a review). a QTL for 2004) they reflectthey the involvement of these d to identify quantitative trait loci osomal regions including genes some 5 QTLs containing the on, or easily-scoredon, (B6) and DBA2/J (D2) (B6) and DBA2/J ations to levels of of to levels ations δ and but nearby, nearby, but ρ α 1 and1 5, 5, β lips et et lips 3 and and 3 ρ 2). 2). re re Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This A potentialA the of using weakness BXD mouse lin be be confounded by compensatory plasticity of GABAergic si onfocus alcohol.literature Most of has the employed cons As far As as weare aware, no studieshave su GABA addictive behaviours. In the following paragra expression have also been used extensively studies, to gene-association Complementary stud Gene2.2.3 experiments: deletion mutation and Drug behavioural traits. This issue has recognisbeen so that BXD analyseswill not provide inform that are andidentical DBA2 between the C57BL/6J suggest that regulation of GABA involved internalisation in receptor is that relating to expression of GABA relating to expression controlalcohol consumption, of ther despite distinct role in humanaddiction.distinct H u g h e s e t a l . , 2 0 1 6 ) i s i n t r i g u i n g a n d s u g g e s t s t h a signal for the In 2004). in rodents (Boehm al., et least behaviours, at GABA mouse strains derived different from eight found beenhave lines developed ( for 2009) that interfered with the ability of ability the with that2009) interfered identify possible to al.,et 2011). However,it was cannabinoid effects that implicates GABA that effects implicates cannabinoid α A A 5 or 5 R genetic manipulationsR genetic in on mice behavi receptor receptor being associatsubunit expression α 6 may indicate 6 a lackthese of involvement genes of inal α 5 subunit5 in human e.g. A receptor subunits. (Williams et al., 2004)). Using Using 2004)). al., et (Williams A receptor trafficking receptor role in the an important play may vs . rodent NAcc (Lingford-Hughes et al., 2012, Lingfor 2012, et al., (Lingford-Hughes NAcc . rodent A β receptor subunits. subunits. receptor 2 subunits2 to interact with adaptinAP-2 protein (Herring These observations thus al., et 2003). ggested a QTLggested for psychostimulant,opiate or to explore the role of GABAergic genes in e beinge little evidence for alcohol drinking ed, and strategies involving multiple founder involvingfounder multiple anded, strategies ation on the involvement of such in genes phs, willwe phs, impact of examine the specific ies employingies direct manipulation of gene (Tabakoffparticular variations SNP et al., ours relevant to drug ours dependence witha es is that for those chromosomal regions ises that for those chromosomal regions ed ed with alcohol drinking was found (Saba /J lines, there can be no genetic variation, er lines, er no for evidence direct altered t s o m e r e c e p t o ri s o f o r m sm a y p l a y a self-administration self-administration this respect, a strikingly more robust a respect, this titutive gene deletion, which may gnalling and of other genes. For a set of recombinant inbred recombinant inbred ofa set cohol-related d- Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This inhibition (as do Experiments attempting to localise these effects of effects these to localise attempting Experiments reported been have conditioning (Werneral., 2006). et induced behavioural effects, but not in al alcohol, without affecting normal GABAergic tr and toLeu277 alanine mutations in the of consequence effects of the deletion may changes reflect in and al.,et 2001), it 50%) (Sur (approximately GABA reportedbeen to result in a substantial (a mechanism mechanisms. del Notably, a torelated DA-dependent Deleting the (sucrose). alcohol-motivated behaviour, but also in oper activity.affect that the data suggest These 23390, SCH antagonist, D1 the and eticlopride, antagonist, alcohol (1.75–3.0 doses that g/kg), an effect (2003) Blednov behavioural’s et (confirming In the June al study, the null et mutants al sucrose-maintained operant andresponding, home In keeping, lackingmice the injection of after Bledno 2003b, al., et alcohol (Blednov consumption, increased aversion to alcohol, α the instance, 2.2.3.1 alpha1. 2.2.3.1 employed tosiRNA suppress 1-subunit null mutant have mice report been A receptor α

α α 6 knockout6 of expression increases a K α 2 and and 2 1-subunit deletion. Neverthe 6-GABA α α 1 subunit1 also appeared tounmask 3 subunit expression (Vicini 3 et A Rs in cerebellar granule cells) (Brickley et al., 2001) al., et (Brickley cells) granule cerebellar in Rs α α 1 gene expression in ventral pa ventral in expression 1 gene 1 subunit1 showedmarked reductions in both alcohol and α 1 subunit1 (which their response alter may to could be attenuated by the dopamine (DA) D2R pproximately 38%) compensatory increase in so showed in locomotor significant increases is therefore unclear whether the behavioural and a and a stimulationmarked motor of activity α less, in knock-in mice with Ser270 to histidine Ser270 in histidine knock-inmice to with less, antrespondingfor a conventional reinforcer ed ed to show decreased alcohol and saccharin cohol consumption, or place preference these receptors,these than rather being a direct findings) after injections of low–moderate injections of low–moderate after findings) 1-GABA ansmission), alterations in specific alcohol- -cage alcohol drinking alcohol drinking -cage α v et al., 2003a, Boehm et al., 2004). al., et Boehm 2003a, al., et v A 1 deletion to brainspecific deletion 1 areas, al., 2001) and immunoprecipitation immunoprecipitation and al., 2001) R may play an important role in role important playmay an R at doses that themselves did not not did themselves that at doses + alcohol's stimulatory effects, by channel thatincreases channel tonic llidum of high-alcohol llidum of high-alcohol drinking etion of the (June et al., 2007). 2007). al., et (June α . . 1-subunit has Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Butkovich et al., (2015) then asked whether asked then the al., et (2015) Butkovich A recentA study examined cocaine self-adminis GABA respect. respect. al., et reinforcer (Stephens for a conditioned induced reinstatement of responding, a measure which rese extinction (in which the knockdown resemble though following training achieved they similar infusion learn a discriminated nose-pokeresponse to obtain intraven delete delete infused during adolescence into early the 2011). al., et unaffectedintake were (Yang water rats, andin found binge drin decrease a marked developing instead developinghabit-like instead behavi GABA performance of goal-directedresponse strate GABA PFC orbitofrontal that suggests 2015) al., strategies, but not in performing them. parallel A f report administration following administration following responses to the reinforced response. Thus, adulthood, the Gabra1 mice knockdown did not in action-outcome when learning. However, similar manipul in persisted mice knockdownGabra1 performing re biased their responding to the contingent random, and thus independent of the instru dissoc was responses of the one reinforcers, perfor to trained mice initially were which association thebetween instrumental response and the cocaine A A A receptor tone may be necessary in tone receptor bemay de necessary α α 1-expressing genes in this in genes (Butkovicharea this 1-expressing 1 knockdown unablewere knockdown 1 to actions select based on their c Gabra1 knockdown might reflect impa reflect might knockdown oural inflexibility. Thus cortical Thus inflexibility. oural medial prefrontal ofcortex floxed a healthy medial prefrontal cortex (PFC) m twom different responses to obtain food 2010), but the groups did not differ in this in this did not differ groups the but 2010), sponse that continued to deliver food, the mental response). While control nowmice iated from food delivery (which was made gies. Mice with orbitofrontal PFC-targeted d controls) the mice were tested for cue- king; importantly,king; binge sucrose drinking, or both responses, suggesting an impairment tration, using Cre-expressing lentiviruses lentiviruses Cre-expressing using tration, slower rate of acquisition of cocaine self- slower rate differ from controls in distributing their veloping goal-directed decision-making veloping goal-directeddecision-making al., et 2015). Suchwere mice slower to A A α 1 silencing similarly the impairs silencing 1 rom the (Swansongroup same et mbles instrumental responding mbles instrumental responding rates to controls. rates Following ations carried were out in reinforcer. Using in a task ous infusionsous of cocaine, ired ability to learn the the to learn ired ability α 1 GABA 1 Gabra1 onsequences, A receptors mice mice to α 1- Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

Self-administration of cocaine was also unaltered in unaltered was also Self-administration of cocaine On the other hand, Blednov and colleagues (B BlednovOn the hand,other and colleagues Given the Giventhe implicating evidence the GABRA2 gene, encodi alpha2 2.2.3.2 of extinction. These observations suggest strongly that dose of cocaine, or cocaine-associated stimuli toacquire operant intravenous self-administration of cocaine, dose-responseextensive and KO study, WT, hetero administrationin of abused drugs animals wi addictions, a number of have studies investigated either apparent discrepancy are not understood, but it but not understood, are discrepancy apparent indicates that Curiousl ataxia. to induce in the ability of alcohol part tha indicating mice, knockout the in enhanced markedly containing GABA observation2012).This al., suggests that alcoholreinfor alcohol at similarrates, with nodifferences in p r e s s e s r ereceive increasing concentrationsofon alcohol q u i r e d t o oevidence that b t a i n o n e r e w a r d ) ; b o t h W T a n d whetheraspects these be may to allgeneral rein fl learning and test in instrumental to be important appear mutating mutating background. x Sv129/ev mixed C57BL/6J onmaintained a study had been backcrossed to C57BL/6J, while those in of hadmice derivedbeen from the identical founder mu necessary for the reinforcing properti the reinforcing for necessary α 2 subunits (serine to 270 histidine (serine subunits 2 leucineand to 277 α α 2-deletion against protect may alcohol- 2 knockout2 differedmice from wild ty A receptors. However, the ataxic and sedative effects of al of effects sedative and ataxic the However, receptors. es of either cocaine or alcohol. the reinforcersnumbers earned of (Dixonet to reinstate self-administration after a period a after self-administration reinstate to an FR4reinforcement schedule of (four lever th deletions of this forcers, and not only to drugs of abuse. may be important that bothalthough sets lednov et al., 2011) did find effects of effects did find 2011) al., et lednov zygous mice did not differ in theirabilitydidzygous micenot α y, another report (Boehm et al., 2004) 2004) anothery, al., et (Boehm report pe (WT) mice when pe (WT) mice lever-pressing to 2 KO mice (Dixonet al., 2014);in an induced ataxia. The reasonsinducedthisataxia. for The our study (Dixon al., et 2012) were k n o c k o u t m i c e s e l f - a d m i n i s t e r e d t t tants, those in the Boehm et al α cementdoes not require α consumption,operant self- or ng theng 2-GABA 2- 2- GABA exibility, though it is unclear unclear it is though exibility, or in the ability of a priming priming of the a or in ability alanine mutations) that that mutations) alanine receptor. We foundno We receptor. A α receptors may play a play may receptors 2 subunit,2 inhuman A receptors are not are receptors cohol were cohol were α 2- Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

Two other studies have investigated the role of GABA the investigated have Two studies other alpha5 2.2.3.3 responding for alcohol be mediated by may 15-4513 by Ro GABA pressing (Stephe for sucrose was unaffected pressingfor alcohol/sucrose in but WT mice, had less containing the agonist, inverse site benzodiazepine 10% alcohol/10% butsucrose, responded less administration. of relevant alcohol effects to alcohputatively behavioural alcohol at GABAergic synapses containing the Th test. nature of the exact depended upon the also demonstrated complexchanges inalcohol the motor sti showedof mutantThese mice loss a complete made insensitive them to potentiation by al reduced reduced alcohol self-administration, from the evidence th sucrose. Although for 4% inverse agon pressing lever effectivemg/kg, corresponding 1 dose of to ov 3 dose-dependentlymg/kg) decreased lever containing GABA that possesses greate alpha5IA-II, of the ability novel a study, same unaffected, suggesting that this effect is not mediated by the However, the ability ataxic effects. of Ro to reduce 15-4513 knockout by alcohol, since no differences were these differences were probably not attributable low alcohol concentrations (2-8%), but consum measures of alcohol consumption, A receptors are are receptors not essential for alcohol reward, but the r

α α A 5 subunit (see Section 2.1.3). This drug dose-depende drug This 2.1.3). Section (see subunit 5 receptors, to influence operant was studied.responding to influence receptors, 5

knockout mice did not differ from WTs in operantmiceWTs respon from did not differ knockout r inverse agonist activity agonist inverse r at α α 5-efficacy-selective benzod Ro 15-4513, has high affinity for high affinity has 15-4513, Ro GABA 5 knockout5 did mice from differ WT at not ns et al., 2005). These data suggest ns et 2005). dataThese suggest that al., cohol yet retained normal GABA sensitivity. cohol normal retained yet sensitivity. GABA er 90% receptor occupancy, but did not affect affect 90% not occupancy,receptor butdid er for 10% sucrose (Stephens et al., 2005). The 2005). al., et sucrose (Stephensfor 10% intake and preference the directionofwhich ese ese studies demonstrate that the effects of α to increased behavioural disruption of the pressing for 10% alcohol, the minimally seen in sensitivity to sensitivity in seen or alcohol's sedative ed less ed less alcohol at higher concentrations; 2 subunit2 may be important for specific A ists acting at receptor subunits receptor in alcohol self- effect ineffect olism. is studyis that it unlikely is indicates mulant effects of alcohol, ofmulant effects and

α α 5- than at alcohol consumption was 5-GABA α iazepine receptor ligand, α 5--GABA 5

eduction of operant knockout mice; lever lever mice; knockout α 5-GABA A ntly reduced lever lever reduced ntly receptors. In the Alpha5IA-II (0.03- Alpha5IA-II α A receptors.In 1-, 1-, A A α receptors receptors 2- 2- or ding for ding for α α 3- 5- Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This conclusion effi the potential similar regarding A

A numberA haveof studies used the atypical 2.2.3.4 More persuasively,More alcohol lowered intake was

consumption is by provided (Ruedi-Bettschen is consumption as an ethanol antagonist, and wasas an ethanol antagonist, and thought tothis achieve effect of function XLi-093. antagonist The changesdrinking.in alcoholredrinking could be the maintained self-administration. The behaviour typical of alcoholConcen intoxication. 90 from ranging levels alcohol blood relevant group trained animals to self-administer 6% al al., 2005). that alcohol reinforcement in mice requires activation of the the transmission adenosinergic of involvement the not reflect may 2011) of devoid regions point mutation in the is lost in the brains of4513 binding rende mice the effect was seen only in mice.male Howeve in absent ethanol-induced ataxia is this is pr interpretation detailed for 2007) al., et but (Korpi see 2006); GABA δ α -subunit, and these animals a also showed animals and these -subunit, A 5-GABA Rs, putatively involved in the actions of ethanol (Hanchar et putativelyRs, involved in the actions α 4 and and 4 α 4-GABA A receptor inverse agonist L-655,708 i receptor agonist L-655,708 inverse δ subunit containing receptors. (Linden expression subunit al.,et A Rs inalcohol behaviours. related Thiswas drug initiall ovided bydata indicating that the 2 subunit (F77I), and, moreover, Ro 15-4513 binding i binding moreover, Ro 15-4513 and, (F77I), 2 subunit (Meng and Dar, 1994). and(Meng 1994). Dar, α α 4 knockout mice (Iyer et al, 2011), though, curiously, 2011), al, et knockout (Iyer mice 4 5-GABA α4βδ benzodiazepine, Ro 15-4513, to investigate the the to investigate 15-4513, Ro benzodiazepine, to 160 160 to in which produced changes mg/dl, and A red insensitive to this atypical BZ ligand by a BZ ligand a insensitive red to this atypical by receptor agonist QH agonist receptor et al., 2013). Using rhesus monkeys, this this monkeys, rhesus Using 2013). al., et receptors, but instead may possibly involve receptors, but instead involve possibly may r, approximately 90% of high affinity Ro 15- affinity approximately r, 90% high of discussion). Some evidence in with keeping evidence discussion). Some cohol sufficient to reach pharmacologically pharmacologically reach sufficient to cohol cacy ofcacy inverse agonists in reducing alcohol in mice a constitutive carrying knockout of ttenuated withdrawal from chronicalcohol ttenuated trations ofsucrosetrations 3% also 0.3 to reliably nhibited, alcohol-, but not sucrose- nhibited, versed with the versed 2011). Thus, the data of Iver et al al et Iver of data the Thus, 2011). ability of Ro 15-4513 to antagonise α 5-GABA via an action at A al., 2006, Wallner et et al., Wallner al., 2006, receptors receptors (Stephens et -ii-066 enhanced, and α 5-GABA y characterisedy s prominent in s prominent in A receptor receptor α 4/6 βδ - Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

In keepingIn with association of alcoholthis with drinking mentionedAs already, constitutive knockoutmice provide a of neurons ( GABA of themedial shell did not affectintakea 2% of shell, or in the core, the lateral the of knockdown inreceptorsfor or necessary the NAcc are of the NAcc in regions localized RNA (RNAi) tointerference expression reduce of the GAB or to specific neuronal and Nie classes. colle gene manipulationas limiti inadulthood,well as More of the brain.effective rece in all parts (potentially allowing compensatory changes in the contribution to of behaviour, genes toler acute and chronic both developed mice knockout the a normal anxiolytic response to alcohol and a exposure (Mihalek al., et 2001). It is of intere not altered during the initial 5 minutes of thebu session, wasagain notfor sucrose altere the NAcc shell, but not in core.NAcc This reduc α RNAi that virally-mediated showed further (2012) al., 2014). amediate to GABA tonic inhibitory th current extrasynapticpresence of (MSNs), using both immunohistochemistry and electrophys Ind 2008). al., et Peden al.,et 2013, (Herd subunit associates with the 4 GABA4 A A receptor receptor subunit, also significantlyalco reduced for responding e.g. thalamocorticalneurons, hippocampal gyrusdentate granule ce -subunit in the medial shell of region but the NAcc, not -subunit reduction are spec reduction are -subunit α 4 β α 4 subunit4 and a reduced alcohol intake. In contrast, receptors, that activated receptors, are by ambient concentrationsof d. Interestingly,responding during reinforcedsessio to test the hypothesis that ntly,techniques developedbeen have that allow as the gene is absent is gene as the during development st thatthesest effects be dissociated could from agues used the technique of virally-mediated eed, in medium spiny eed, mouse NAcc neurons normal hypothermic response to alcohol, and sucrose solution, suggesting that the effects at neuronal reduces excitability (Maguire et al alcohol consumption. foundThey that expression well of genes), other expression being as as ific to alcohol (Nie to alcoholific (Nie et In a variety al., 2011). ng the manipulation to discrete brain areas, β tion specific to alcohol, was responding as that transiently reduced expression of the of the that transiently expression reduced subunit to form extrasynaptic receptors A ance. ance. α A A 4-GABA receptor receptor blunt instrument for analysing iology, demonstratedwe the t decreased after 5 minutes, -subunit-containing GABA hol after A receptors, Rewal alet -subunit in knockdown -subunit in adult rats α in the or ventral 4 reductions in reductions 4 lls)the ns was was ns A

facilitate or it. recently reduce We facilitate investig receptors playin a role regulation of alcoho thisofWhile series studies suggests stro 2014). Boehm, intogaboxadol cortex infralimbic was reported could throw light onhypotheses. these In contrast to the N may whichoccur, would not be the case for th of that in the case account is possiblefurther shifts to either the leftright ofoptimal or the may res response functions for alcohol consumption e frequently estimate local concentrations in experiments us firstly, gaboxadol at high doses is not specific for of explanations potential two suggest colleagues et Ramaker 2012, al., et (Ramaker alcohol intake decreases the while facilitating 2012), al., et Rewal al., 2011, et (Nie using receptors tonically-active extrasynaptic decreased consumptionalcoholin of 10% that gaboxad found et 2015) (Ramaker al., study, the group same administration as well as shifting patterns the drinking in bo paradigms, altering both the consumatory dependently alcohol decreased intake in bo al., et 2012) (Ramaker studies interference apparent disagreement with the observations on made the GABA of extrasynaptic agonist The drug gaboxadol,when used at appropriately low concentr induced point mutation of the the inducedpoint mutation of GABAergic receptors in mediating alcohol intake, using mi manipulation did not initial alter motivation for alcohol. (R reinforced responses multiple following A receptors containing the the containing receptors β 1 subunit. a 1 leucine-to-arginine This mutation, exchange ngly that extrasynaptic tonically active ngly found found in C57BL/6J thatmice gaboxadol dose- viral knockdown alcoholreduces consumption gaboxadol infusions, receptor desensitisation l consumption, it is not clear whether they they not it is whether clear l consumption, e knockdown.e are We not aware of data that ated the potential role of tonically active active ated the role of tonically potential and appetitive of processes operant self- ewal et al., 2012), suggesting that the that ewal al.,et 2012), suggesting th two-bottle choice, and limited access access th two-bottle choice, and limited to increase alcohol consumption (Fritz and and (Fritz consumption to alcohol increase a limited access test.inactivating Thus, ing intra-striatal infusions; secondly, dose- these apparently incompatible data sets; apparently incompatible data sets; these α4βδ xhibit an inverted-U shape, so that ult in consumption. decreased A ce with an N-ethyl-N-nitrosourea- δ receptors, and it is difficult it receptors, is and to subunit (Belelli al.,et 2005). In Acc injections,Acc administration of ir function with gaboxadol also also with gaboxadol ir function th procedures. In a subsequent ations, as a selective acts ol infused into NAcc shell, ol infused al., 2015). Ramaker and 2015). Ramaker al., α 4 and4 subunit gene α4βδ GABA A

Thus, insummary,while manipulations of particular subun activity. GABAergic are we However, unaware of evidence suggesting a selectiv antagonised by co-administration of the GABA reinforcement by terminating responding after a perioshort administrationGABA of the underlying satiety to alcohol. facilitated satiety). Thus more rapid decrease in responding following multiple r α correspond might finding to the (Rewal which et operant responding suggested to pr the session as consumption, and pressing, obtain alcohol,even to intoxication; in contrast, WT mice to p rise gave mutant the L285R Furthermore, experiment. consumption of (butalcohol not sucrose,of inseen was a spontaneous mutant, the NAcc (i.e., resembling tonically receactive increased GABA sensitivity of recombinant GABA spontaneous GABA linker, an important receptor for GABA ac area (L285R) in the highly-conservedthird transmembranedomai receptors. receptors. con tonic of by modifications exerted behavioural alterations, most consistent effects 4-containing GABA A A receptor receptor ionchannel opening ( receptors showed no changes in in , tonically, GABA active A agonist, muscimol, operant reduced respondingfor ethano I n t h i s c o n t e x t , i t i s o f us that the mutation led to a failure to satiate to alcohol, Gabrb1 ductance,including of by manipulation saccharine,in a two-bottle choice or quinine) ogressed (Anstee et al., 2013). The pattern of of pattern The 2013). al., et (Anstee ogressed +/ A ptors). A similar electrophysiological pattern pattern electrophysiological similar A ptors). A antagonist bicuculline (Hodge et al., 1995). 1995). al.,et (Hodge antagonist bicuculline tivation and ion channel gating, resulted in resulted gating, and ion channel tivation P228H on motivation to obtain alcoholbe to seem al., 2012) that virally-mediated reduction of reduction of virally-mediated that 2012) al., receptors may play a role in mechanisms mechanisms in role a play may receptors A Rs, coupled to increased tonic currents in . Both mutants showed an showed Both mutants i.e itialalcohol, for responding but a . in ofthe absence and GABA) ersistent operant responding to responding operant ersistent interest that intra-accumbens that interest einforcers ( e actione of muscimol on tonic d of that an effect time, was n (TM3), nearn the (TM3), TM2-TM3 its ofits GABA reduced their rate of lever i.e., A R s g i v e r i s e t o suggestive of increased α4βδ l

Many studies incorporated have of measures Chronic2.3.1 exposure: drug alcoho In principle, genetically influenced predispositi 2.3. ofInfluence abused drugs on GABA

chronic alcohol treatment (see re (see treatment chronic alcohol toprotein levels. be extrapolated necessarily limite was this as study However, effects. chr X and most of the chr 5 subunit loaded genes were imp sensitive to the effects of alcohol/cocaine. In with alcohol a associated previously cluster, notably involved insynthesis andGABA those synaptic trans al., (Enoch analysis et dependence. factor A increasesdrugs the likelihoodincreasingvoof intake. Thus, to to drug in the ability adapt highlighted by the authors, these adaptationsthese basolateralauthors, highlighted in by the amy approached statistical significance, with noin changes were significantly decreased, whereas decreases in the Th month-long al., exposure et 2004). (Floyd to alcohol fascicularis expression were found. Similarly, an impr change in accumbens,wasin although a decrease there 28% of expression of both these (Papadeas chan 2001). However, al., et by ofweeks after immunoblotting chroni two ra in decreases For instance, al., 2000). et ((Grobin changesand directionof course time in s α ), quantified GABA 1 1 subunit expression; in the VTA, no in changes either α 1 and1 α A

4 subunits4 decreased was while in the by about 20%, α view et by (Kumar 2009)). al., subunit mRNAs in basolateral amygdala following 18- amygdala insubunit basolateral mRNAs ,ccieadmtapeaie methamphetamine and cocaine l, A receptor subunit expression essive essive withstudy cynomolgus macaques ( nd drug dependence inhumans, themselves are d to expression, mRNA the findings notmay ubunit expression across varies brain regions contrast, the two factors on which the chr 15, 15, chr the which on factors the two contrast, for instance, the development of to tolerance for instance, the development 2013) revealed that distinct groups of genes, of groups genes, distinct that revealed 2013) on to drug taking may result from differences luntary drug intake, which may then result in mRNA or subunit peptide levels following c exposure c to alcoholhave been reported ges were region specific; in amygdala, region wereges in amygdala, specific; t α 1 and and 1 α 4 subunit expression, there wasexpression, no there subunit 4 e e α 2 and2 port and members of the chr 4 α α

4 subunit4 As levels. mRNA 4 subunit 4 expression assayed α In general, In general, the occurrence, 1 1 only expression subunit ervious to alcohol/cocaine gdala GABA gdala α 3 subunit3 mRNA levels α 1 or or 1 A receptors are α 4 subunit4 Macaca Macaca Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Considerableevidence indicates that ne

A numberA of additional studies also document ho However, the alterations in excitatory transmis (Conra calciumaltered permeability transm synaptic receptor-mediated AMPA of strength the in becomingstable, and then declining. be These cocaineintensification to obtain motivation of cocaine changes over time, in keeping with experimenter-administered patternscocaine. The GABAergic transmission in the NAccshellis diff (Wy report and a recent 2010), animals and(Wolf Ferrario, administered cocaine differ from such responses when th section 3.2.3). section 3.2.3). excessiveDAassociated tone to with exposure prolonged compwhich represent may a al., 2008) (Heiman et (Suzuki et al., 2000). Of Of 2000). al., et (Suzuki mRNA expression pattern have been documented following albe 2006)). Moreover, similar, al., (Hemby et GABA lowered was expression present priorto onsetalcoho of with subjects, control though in the human cohort, no it is encoding the receptor subunits investigated in the cent inmortem alcoholic(Ji foundbeen patients also post has wi In agreement al.,(Papadeas et 2001). but similar, not identical, described in to those decreased expression of receptorsin behaviour, addictive chronic tr cocaine treatment in mice resulted in an up-regulation of A A receptor subunits are very much dependent on the brain re the much dependent on very are subunits receptor α 2 subunit2 significantlydown-regulat was α specific relevance specific relevance and in keeping with for role a 2 subunits2 In (Chen in al., et 2007). the NAcc contrast, c d et al., 2008, Mameli et al., 2009, Loweth et al., 2014). 2014). Loweth al., et al., et 2009, Mameli 2008, d al., et th the macaque data, macaque down-regulationdata, ofth the ral of nucleus only the amygdala, the mRNA eatment of rodents in with cocaine of eatment results urobiological responses to experimenter- responses urobiological rodents after a brief forced forced after a brief rodents alcohol exposure (incubation) lasting for lasting (incubation) before weeks, several haviouralchanges areparalleled by changes sion do not seem to be paralleled by altered by altered paralleled to be not seem do sion it not identical, it not identical, scenariosof altered varied erentiallyby affected self-administered and w changes changes w in the expression of a variety of behavioural changes indicating changes initial behavioural of change of inreceptor function following ensatory brake that limits the effect of the an effect that limits brake ensatory l abuse. ed ed in alcoholic patientscompared α t possible to deduce whether the e cocainee is self-administered by 4 mRNA specifically in D1-MSNs in D1-MSNs mRNA4 specifically dra et al., 2013) indicates that al., indicates dra et 2013) the the psychostimulant also (see n et al., 2014); of 19 GABA 19 of n et 2014); al., chronic exposure to cocaine ission in NAcc mediated by by mediated NAcc in ission gion investigated ( α 2-containing α 2 mRNA mRNA 2 hronic e.g. A

2.3.3 The of ageinfluence 2.3.3 (develop Cl mediated response switch from to inwardly outw alteration, upon subsequent reverse may wi expression (Shen however, alet 2013). Note, appeared to be affected by chronic ex subun Interestingly, a similar Liang al., et 2014). 2014, Spige al.,amygdala of et Olsen and CIE (Cagetti rats 2003, inincreases coordinated decrease in electrophysiological and immunoblotting a pattern of drinking. Us of this features of the of rodents to chronic inter Exposure 2003). Duka al., et brain structure and behavioural competence (Stephens and Du pattern whichhas been shown particularly to be combine such high oflevels alcoholbi during Alcohol-dependent individuals oftenconsumeal exposure: drug Intermittent 2.3.2 alcohol that this that this sensitivity is especially whensevere It is widely held thatadolescent mammals are GABA intake over the first of few self-administration, days intake over (2014) al’s is in with keeping Dixonproposal et co excessive be a protective against mechanism withdrawal day 25 or withdrawalor 48. chanNo day 25 suggestive of increased inhibitory this tone, change was tr receptorsubunits was initiallyincreased(on second the observed at anyobserved time. The author - ions transporter expression also(see se A receptor receptor function (Purgianto al., et 2016); although surfac γ 2 and and 2 α 4 subunits4 (both synaptic) in hippocampus, accumbens and α 1 (synaptic) (synaptic) 1 and s suggest that upregulation ofsuggest s ment) on ment) the effects of alcohol ges in ges expressionsurface of posure to methamphetamine in rodents, ction 2.3.4 on Functional alterations). ction on Functional 2.3.4 alterations). pproaches have revealed a consistent and havepproaches consistent revealed and a nge episodes episodes nge andexperience of withdrawal, a ing this model, a series of reports combining combining reports of series ing this model, a particularlysensitive and to alcohol exposure, exposure is intermittent,such as occurs in observation that while WT mice reduce drug reduce mice while WT that observation δ thdrawal because the polarityof the Cl subunit (extrasynaptic) expression and deleterious, resulting in marked changes in in marked changes deleterious, resulting cohol in bouts of excessive drinking, which drinking, excessive of bouts cohol in that the functional consequences of this caine taking (Purgianto et al., 2016). This 2016). al., taking et (Purgianto caine ardly asdirected a result of alterations in α2 it set, it set, namely

mittent alcohol (CIE) replicates some (CIE) mittent alcohol knockout mice do not. mice knockout ansient and no longer detected on lman, 2012, Lindemeyer et Lindemeyer al., et lman, 2012, day of cocaine withdrawal), day of cocaine ka, 2008, O'Daly et al., 2012, al., 2012, et O'Daly 2008, ka, α e e expression of 2-subunit expression may α

1 or or 1 α 4 β α GABA 4 subunits were subunits4 were i.e basolateral A . increased receptors receptors α 2-GABA A -

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This α i for example, an Thus, al.,et 2014a). Grabenstatter 2014, oftypically tempor models in recorded animal affected, albeit not necessarily in dire the same for two reason observations intriguing These are uponexposure. drug α intermittently to drugs of A abuse.common of GABA illu limited of studies exemplar selection This the GABA exposu intermittent alcohol (CIE) normalized 26 days AIE. after In to the contrast effects of changed by and although AIE, (but not 48 hours) the after last AIE exposure. The subunit protein significantlywere levels reduced at both 48 and 26 hours the after last days alcohol exposure significant reduction in the betwee exposure intermittent alcohol (AIE) one subunit( in any GABA changes data is the diversity of responses in different tissues. T McBr McBride al.,al., et 2015, 2014, et (McClintick blood overmg/dL, reaching of 100 levels alcohol-preferring following rats P three week Indiana group have reported a series of observ (Stephens and Du drinking binge with humans molecular changes are are changes molecular associated with a reduction in ph frequency high seizur of exhibiting a animals ap of temporal lobe epilepsy, models animal 1-containing GABA 4, and, to an increasingly documented degree, A A receptor isoforms receptor the brain within receptor subunits examined. subunits receptor β 1) in amygdaloidIn co nucleus.1) central A Rs has been consistentlybeen reportedRs has inthehippocampus dentat A receptor insubunits accumbens shell, and an up-regulati subunit in protein the absence levels of any changes in α5 re re during adulthood had no effect on expression of any subunit levels reduced were mRNA at 48 hours they we n postnatal day (PD) 30 and showed PD46 a a period a spanning postnatal days – 49 28 strates the complexity of strates feature acrossfeature studies is the sensitivity of s consumption of alcohol in a “binge” pattern, al lobeal epilepsy (Scharfman and Brooks-Kayal, es (Gonzalez et al., 2015). Intriguingly, such Intriguingly, 2015). al., et (Gonzalez es pearing specificallyprominent in cohorts of pearing ations gene on altered ations expression (mRNA) in ka, 2008, Smith et al., 2015). Recently, the 2015). Recently, Smithal., 2008, et ka, ction, by the experience of epilepticeventsexperience of ction, by the s. Firstly, subunit the same appear clusters , but mRNAlevels but, increased, were 26 days of animals exposed chronically and/or ide et al., 2013a). Striking from this set of set from this Striking ide al., et 2013a). α 2 and2 α ntrast, ratsntrast, subjectedto adolescent 5 5 subunit protein notlevels were asic (i.e. synaptic) inhibition, asic (i.e. which synaptic) hus, three these foundstudies no ncrease and decrease in in and decrease ncrease (Centanni The et 2014). al., 2 2 subunits to dynamic changes the altered landscape landscape altered the chronicAIE, on of only e gyrus ofgyrus e α mRNA, 4- and 4- and α α re re of 1, 1, 4 4 Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This GABA in Alterations 2.3.4 solubilitylimited issues raises experime for in vivo rega In this exploited to therapeutic advantage. ma selective Thus, Section 2.2.3.4). et Maguire et (Anstee 2013, receptor al., channel activity increased alcohol consumption in two mouse models of i tonicknown inhibition, as toni andincreased Secondly, pilocarpine temp in the respectively, seizures long-termreduces seizure frequency or the delivery dentate via a viral-mediated gyrus hippocampus of inhibition early selective of STAT3, which me GABA could to be targeted therapeutic (seeadvantage alsosee paragrap andin Brooks-Kayal, (Scharfmanreviewed 2014) repressorelement and earlygrowth(ICER) factor response of BDNF regulation (e.g epilepsy neuronal GABA However,raises the prospect it that molecular mechanisms Bec Stephensal., 2001, (Finn al., 1995, et seizures et withdrawn from animals between relationship thisWhether putative commonality of plasticity independeis reminiscent ofdescribed aboveanimal those for and Broo (Scharfman receptors has putativelybeen assigned to an increased contribution by Cl GABA In addition to changes in the expression of spec -GABA - flux has describedbeen for GABA α 1 expression (Grabe expression 1 A A R function below R function and Conclusion Section reg 5). In this R function associated with drug exposure anda ch associated withinvolving drug function R A A receptors may may et receptors be of (Wafford interest α 4 β A GABA R-mediated adaptations described for A receptors are known to mediate mediate to known are receptors A nstatter et al., 2014b), or increased or increased et 2014b), nstatter al., R function. ks-Kayal, 2014, Gonzalez et al., et 2015). Such changes Gonzalez 2014, are ks-Kayal, α 1 and1 nipulation of this specific GABA specific of this nipulation A receptors in the interneurons, but not DA neurons, of of neurons, DA but not interneurons, the in receptors α 4 subunit4 expression diates upon BDNF ICEReffect down-regulation number of animals experiencing spontaneous ific receptor subtypes,a distinct inalteration rd the drug whichrd the drug DS2, is a of PAM selective maydrug also be addiction to relevant and c inhibitionc in the associatesNAcc with s exposed s to chronic intermittent ethanol. nts. alcohol and their sensitivity to epileptic oral lobe epilepsyoral lobe model intriguing. is al., 2009, Jensen et al., 2013), though its et Jensen al., 2009, its though al., 2013), ker and Hale, 1993) is not known. known. not is 1993) and Hale, ker animal models of temporal lobe lobe of temporal models animal al., 2014, Rewal et al., 2012) - see see - al., et 2012) Rewal 2014, al., a sustained inhibition form of approach (Raol et al., 2006) approach 2006) (Raol al., et akinimplicatedto those in the

(Egr3) pathways(Egr3) respectively, ncreased spontaneous GABA α 4 via β ard, the observation that α inducible response cAMP ange in the polarity the of ange 2- over over 2- nt of the documented 1-subunit expression in A receptor tone receptor be may h 2.3.4 Alteration in α 1 β 2-containing A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Addictive drugsAddictive theabilityshare to influence the function A detailedA discussionof the neuronal substrates 3. 3. GABA therapeutic targeting (Friedel et thus and 2014), 2010, al., et transporter al.,et Kaila (Lee abnormal to trigger operate GABA thereforeconcei It is 2016). al.,et Kahle neuropathic pain models (Pathak et Zh al., 2007, the polarity of the GABA of alterationin GABA directed Cl in not affected is signal GABAergic Importantly, the 2016). GABA Cl KCC2,transporter thus causing induced glial release of BDNF, that results in a decreas imp a potentially revealed recently colleagues Taylor and the VTAin of opioidinhibitory to excitatory Following the VTA. an initial report document the NAcc with the NAcc signalsother mediated by from DA n released cortical and amygdala hippocampus, the including conveyed in the form of, prim and val availability temporal and spatial information about the this neuronal circuitry (Fig a ro central 3), implicatedin mediating control motivati over pharmacological manipulation.pharmacological described to highlight areasrelevance of specific to However, an overview of the ne 2 Everitt Robbins, and (Silberberg and Bolam, 2015, topic beyond scope of this review the and readers are referred A A receptor activation,receptor thereby giving to rise A receptors in the neurocircuitry of addiction addiction of neurocircuitry the in receptors - gradient appears to be maintained independent of KCC2. Intri A A receptor functionreceptor is not unique to dr A A receptor-mediated signalshas beendescribed for epilep arily, glutamatergicarily, inputs originating in specific structu al., 2015, Kahle et al., 2016). Kahle et al., 2015, urocircuitry implicated in addi urocircuitry implicated - A ion to become net movement outwardly upon directed receptor function, mostnotably, phosphorylation receptor of the vable that similar molecular mechanisms may may mechanisms molecular similar that vable -dependent rats (Vargas-Perez et al., 2009), 2009), al., et (Vargas-Perez rats -dependent onal aspects of complex behaviours. Within behaviours. of complex aspects onal le is played by the NAcc, which receives whichplayedreceives le is by the NAcc, ing the switch of the GABAergic signal from implicated in drug abuse and dependence is ou et al., 2012, Barmashenko et al., 2011, 2011, al., et Barmashenko 2012, ou al., et areas. This areas. information is in integrated neuronaldepolarisation (Taylor al.,et offer an opportunity for a selective anoffer opportunity for a selective to comprehensive reviews on this of mesocorticolimbic the system ug addiction as a similar switch in switch in a similar as addiction ug DA neurons, where an inwardly where neurons, DA ed expression of the K GABA 013, Koob and Volkow, 2010). 2010). Volkow, and Koob 013, ortant role played by opioid- role played by ortant ctive behaviours will be briefly briefly be will behaviours ctive eurons projecting from the eurons projecting from the A receptor function receptor and ue ue of specific rewards, guingly, guingly, this type + sy andsy Cl - co- res, res, Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

shown in Fig 3. in Fig shown distinct GABA distinct motivational little atte received had pathways specific behaviouraloutputs. Nevertheless, until pathwaysthese (Fig offering 3), a point of re Partanen, 2015). Accordingly, GABA Accordingly, 2015). Partanen, and substa dorsal striatum the VTA, notably and a variety of in interneurons the in located approximately neuronsNAcc 97%of (both the pr role as plays fundamentalGABA a assembly, striato-nigral and the indirect striato-pallidal routes. Withi output to adjusted the inputs received, than themselves rather the positive or negative events (Schul toadapting provide the corresponding activity response to unexpected events with negati towith unexpected events positiveresponse va midbrain VTA. ventral DA These neurons have implicbeen cellular domains, suggesting the possibility of a the possibility spatially cellular domains, suggesting MSNs and 2) the expression1) of relevance within the context addiction of drug functionreceptor in the motivational neuroc α but populationsin in specific of also MSNs, studies, the role. receptorAmongst additional isoformsrole. by inferred noted that al et Lingford-Hughes 2000, al., et Pirker 2012, representationGABA of the A schematic, striatum. into areas from these projections populationsof cortical, hippocampal and amygda 1 β 2 isoforms isoforms 2 in and dorsal NAcc striatum and in VTA pl MSNs, α α 5 A 2 β receptor isoforms are expressed expressed are with isoforms receptor β α 2 and2 2 2 and and 2 α β 4 β 2 isoforms2 within synaptic and extrasynaptic cellular domains α subtype localizationwithexclusively extrasynaptic no its 2 β α A 1 1 prominentsubtypes1 are and in amygdala the NAcc (Kalk al. et receptorimportancecircuits isoformsof within in addi β 2 isoforms2 additionally are expressed within neuronal A receptors are expressed at locationswithin at significant expressed are receptors via terneurons in the NAcc (Maguire et al., 2014). et 2014). terneurons in the NAcc al., (Maguire ntia nigra and Han, and(Walsh Morello 2014, two the so-calledpathways, classical direct terconnected input and output regions, most gulation for neuronal function and, thereby, to environmental predictingcues such events ircuitry. Amongst the isoforms of particular ircuitry. the isoformsparticular Amongst of ve (aversive valence events), and rapidly ntion. In commonwith other brain circuits, (see Section the functionally 2) are detected recently, this fundamental fundamental recently, role of GABA this in ., 2012, Wisden Wisden al.,et ., 2012, 1992). It should be the the principal neurotransmitter utilisedby incipal neurons, MSNs,incipal neurons, and interneurons), la areas theywhere are likely to influence lence (rewards),lence or decreasing activity in in specific neuronal populations and

in situ controlled regulation of GABA controlled regulation tz, 2016). The NAcc encodes an The NAcc 2016). tz, and/or immunohistochemical ated as increasing activity in n this complex neuronal ay ay a separate important albeit not exhaustive, not exhaustive, albeit t only in only in t of NAcc ction is ction is A , ,

Many of GABA studies self-administration Benzodiazepine 3.1.1 (functional forselectivity administered significantly above vehicle in monke levels self-administer midazolam an drugs.groups of In a second experiment,two compounds included zolpidem,which showspreferential 201 al., et (Shinday intravenous self-administration maintain receptors (' α va that compounds novel of The availability The mechanisms underlying the abuse-relate GABA 3.1 Figure 3 (a compound with functional(a some forselectivity baseline, but not under a cocaine baseline over α benzodiazepines. In a complex of series find humans. In particular, drugs acting at the benzodiazepin the at acting drugs particular, In humans. evaluate abuse potential of novel compounds in development a particular contribution to this area. receptors to have a critical role. role. critical to a have receptors studies several However, opiates,suggest or alcohol. understood, and may a quite represent different substances at particular of GABA subtypes have a reputation for abuse, which potentially 5 subunit-containing5 GABA 1-GABA A A Rs is sufficient, but not necessary, for but not necessary, sufficient, is Rs ReceptorsReward and Drug α 1-sparing compounds') has allowed investigations of investigations has allowed the compounds') 1-sparing A receptor subtypes receptor by the ne motivatedbeen have andreward α A receptors but lack at efficacy 2, 2, d the cocaine.other The α 3 and3 A ry withry to respect intrinsic efficacy at α receptor. The receptor. group ofRowlett James has made 5--GABA ings, the group concluded that stimulation of monkeys used, one were previously trained to d effects of benzodia the the tested.dose ranges Importantly, TP003 type of drug abuse from psychostimulants,type of drug mediation of the abuse potentialthese of may be attributablean to action of such α 3-containing receptors) had significant A Rs), and nonselective conventional α binding to binding e binding site of GABA site binding e 1-sparing compounds self- were ys trainedys under a midazolam α 3, Rowlett et al., 2005). These 2005). These al., et Rowlett 3, α 1 subunit-containing GABA subunit-containing 1 1 subunit-containing1 GABA for therapeutic use in α ir ir differential ability to zepines are notzepines are well 1-GABARs; L-838,417 L-838,417 1-GABARs; α A receptors receptors 2, 2, α 3, and and 3, edto A A A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Although animal self-administration studies studies Although animal self-administration model general very A mechanisms of drug abuse 3.2 GABA 3.2 2008). possess significant maythat also TP003 activity worth noting involvedpsychostimulant be may and in ben neural systems) administration. While these studies that suggest different G ofhistory a in animals compoundstype with GABA monkeys with a history of stimulant self-administration, wher role in the reinforcingreceptors a have may benzodiazepine receptor agonists. The authors suggest that at lower levels albeit reinforcing effects, and current motivational state ( from the intrinsic “rewarding” nature of the dr classesof psychological function,which one of conce only of some whichmay contribute to be to consider genetic contributions to diff many different to ways the developmentaddiction. mor A of alcohol may come about in different ways. Clea alread it has as while, processes, brain different and to drug dependence. Furthermore, addict underlying andpsychologicalconstructs, their mec brain have treated addiction more oras less a unitary concept, it contribute to drug abuse and addictive behaviour in humans drug abuse, failthey to consider many aspe subject to control by higher order functions order impul to control (low higher subject by might contribute in a very large number large very in a contribute might (Volkow al., et Clearly2004)). even within su A receptors may be important mediators of the reinforcing e reinforcing the of mediators important may be receptors A Receptors and processes reward-seekiwith associated e.g. deprived any single individual’s addiction. of output. to ways the behavioural possess considerable “face validity” for human human for possess “face validity” considerable erent aspects of addiction-related behaviour, behaviour, addiction-related of aspects erent vs. cts cts of behaviour and brain function that may effects of benzodiazepine-typeeffects compounds in of self-administration than non-selective ug, memoryof ug, past experience with the drug, ch an oversimplified system, gene variations y been hinted,been y addiction drug like to a single rly, then, genetic makeup may contribute may makeup genetic then, inrly, ions to different drugs may involve rather satiated))while the output this system of is holds that we toneed consider two broad sedative-anxiolytic/benzodiazepineself- rns motivation to obtain drug (resultingrns motivation to obtain drug sivity, restraint, restraint, sivity, hanisms contribute to drug abuse, to drug contribute hanisms zodiazepine it is reinforcement, e profitable e approach thus may . Indeed, although thus far we α at ABA is clear that many different 1 subunit-containing1 GABA eas eas α ng ng ffects of benzodiazepine- ffects 1-GABA A A -receptors (and hence hence (and -receptors α 3 subunit-containing etc A Rs (Peden al.,et . (see .Fig (see and 4 A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This thresholds dose at the highest animals, of diazepam in these w ( to benzodiazepines insensitive ofdiazepam-facilitation ICSS withbyinteracting accumbal GABA Rudolph colleagues postulated and that benzodia of methamphetami effects facilitatory agonistinverse at benzodiazepine receptors, howeve be different.drugs may Note, of the two Invernizzi etthat the indicating al., 1991), me and Impera (Di Chiara concentrations DA decreasing diazepam havecocaine opposite on effects extracellular in DA the effe with 1985) comparable Liebman, al., 1986, benzodiazepine receptor simila ligands) possess understood observations are drugs facilitating that transmiss and (Phillips intracranial self-stimulation transmission in pathways DA (amphetamines, cocaine, are pathways, especially ICSS to likely support “reward”. It has been known that for decades areas within, conclusion that such stimulation area activates preceding the is stimulation strengthened), leading to the self-stimulation; ICSS). By definition, such electrical instrumental in tasks order to deliver electrical It has been the work known since of (Olds In we the next different willsection consider modulation of the authors interpreted to that mean diazepam aversive even may w be 3.2.1 Brain stimulation reward stimulation Brain 3.2.1 to which current knowledgeto which current allows us to impute functional particular functions that might contribute to addictive beha to addictive contribute that might functions particular α 2-GABA A was indeed absent when indeed absent was receptors. However, preventing benzodiazepine sensitiv α 2(H101R) mice) (Reynolds et al., 2012). Indeed, reward Indeed, mice) (Reynolds et 2012). al., 2(H101R) A receptors expressing ne on ICSS (Tracy et al., 2016). al., et ne on ICSS (Tracy Fibiger, 1973, Herberg et al., 1976). Less well well Less 1976). al., et Herberg 1973, Fibiger, and Milner, 1954) that mammals will perform perform mammals will that and Milner, 1954) chanism of action for the “rewarding chanism of effects” for the action aspects of the overall aspects of overall the (Crow, 1972), and that drugs that facilitate that facilitate that (Crow, drugs and 1972), impulses to braincertain impulses (intracranial areas s of the brain integral to the perception of ct sizes (Straub et al., 2010). Diazepam and Diazepam ct (Straub al., et 2010). sizes R o 1 5 - 4 5 1 3 , i s a b l e t o a n t a g o n i s e t h e r propertiesr in enhancing ICSS (Herberg et zepines might achieve their effects on ICSS r, thatr, a recent report indicates that an stimulation is reinforcing (behaviour α etc NAcc, with cocaine increasing and 2-containing receptors were made made were 2-containing receptors viour. viour. ) also facilitate) performancefor α 2 subunits, andsubunits, that 2 showed easy (but possibly mistaken) or interacting with brain DA ion at GABA ion at to, 1988, Finlay et al., 1992, 1992, al., et Finlay 1988, to, roles for GABA as increased, which the system, and the extent extent the system, and ithout the positive ithout the positive A receptors ( A genes in genes ity at i.e.

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This The VTA projections to and the NAcc, associated neural ci “reward” Dissecting 3.2.2 benzodiazepines. GABA specifically in accumbens, using virally-medi further also foundthisstep,in mice in was effect latter w ability to facilitate properties of the rewarding consistentchoiceexperiment, with lo bottle also consumed less midazolam than WT mice when it was pres benzodiazepine, midazolam,also In a subsequent report et al., (Engin the Rudolph2014), effectivenessthe of (Tanarea et tegmental inreceptors ventral participation in transmission GABAergic in Rudolph al., 2010), andcolleagues attribute the involvem GABA effects in manipulationcorresponding of α aspects, so that is DA frequently(and uncritica review). Themesolimbic pathways DA have been ascribed as “incentive” such constructs psychological usedothers the looselywhilea ran to cover is for term occurrences a particular s whenbehaviour, follow that, they dimensionsof such as feelings euphoria, or of relaxati sometimes used as synonymous with pleasure subjective ascribed tothem.In the context of explanat pathways,“reward” whatis frequently unclear though it parti 2-GABA A A receptors inthe are NAcc involvedat leastsome in rewa a significant makes receptors contribution to A α receptors was not unique in altering ICSS reward thresh 1(H101R) mice were reduced. On reduced. 1(H101R) the basis were mice of previou α 1(H101R) manipulation. manipulation. 1(H101R) α 3 also3 abolished the effects of diazepam, while diazepam’s failed to facilitatefailed to ICSS in whileNAcc, the action of diazepam at ated knockdown. These findingsimply that (see (Salamone and Correa, 2012) for a critical a for 2012) Correa, and (Salamone (see sucrose) in the mutant mice. In an important ss of midazolam’s (or effects rewarding ss its lly) referred to as the “reward transmitter”. ions of drug abuse, the term “reward” is the term drug abuse, of ions al., 2010) is speculated to explain the the to explain speculated is 2010) al., GABAergic inhibition in NAcc (Dixon et on), sometimesa synonym on), as for a centralrole insignalling these α (whichseveral itself have may rcuits are often referred to as group confirmedgroup another that ge of more carefully ofdefined more ge ent of the the ent of 2(H101R) mice. These animals animals These mice. 2(H101R) trengthen it ( ented withented sucrose in a two- hich s workthat showing s rd-relatedproperties of cular functionbeing is α 2 had been 2 deleted α 2 subunit to its to its subunit 2 i.e. olds, and the reinforcers), α 1-GABA α α 2- 2- A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Current knowledge suggests that information regarding ince with each other for control over behaviour, behaviour, over for control other each with underlying this integrative process is fundame Un behaviour. motivated express that systems output ganglia the information provided by glutamatergicinput theUnder influence of dopaminergic inputs fr constitute and the only output from the nucl GABAer the of dendrites synapse on the that from prefrontal projections glutamatergic

Two rigorous more considerations of functi DA 3.2.3 The role of GABA of role The 3.2.3 glutamatergic and dopaminergic dopaminergic and glutamatergic signals? biologically valuable events ( events valuable biologically thatholdsoccurs first release DA a pulse of in addiction frequentlyare co Studiesof function GABA easily slipped have in and biologically valuable events ( events valuable biologically and learning associations between otherwise neutral environme al., 1997). In that context, has DA been referred to as a “ soon shifts to environmental stimuli that precede (and thus worth considering how be involveworth may systems GABAergic considering approach to understandingventral striatalfuncti Cag Cagniard 2014, al., et 2006b, al., et Hart al., 2016, function,while tonic mayrelease act to energise rough distinction, phasic DA release has been suggested (S (see of motivation aspects proposed to energise goal-directed behaviours, is anrelease important consequence. Secondly, relea DA association must occur somewhere other thanwithin the sy DA A receptors within mesolimbic pathways: a hub for in hub a pathways: mesolimbic within receptors alamone and Correa, 2012) for a review). In keeping wi keeping In review). a for 2012) Correa, and alamone nsidered in termsnsidered in of to modulate their ability “reward”. e.g. unexpectedlyobtaining a piec e.g . dinner), though, in reality the learning. dinner), though, in of that yet yet knowwe of little its detailed mechanism. cortex, thalamus,cortex, hippocampus and amygdala eus (Tepper et al., 2008, Tepper et al., 2007). 2007). al., et Tepper eus (Tepper 2008, al., et gic MSNs that make up 95% of NAcc neuronsNAcc thatof gic MSNs make up 95% in the context of unexpected occurrence of on worth are considering in this context. The ntal to how describing motivations compete to this thinking, so that to this thinking, so GABAergic influences om the VTA, these MSNs sort and prioritise s and project thes output integrated to basal selected goal-directed behaviour(Hamid et i.e., on, and its roleon, and its in addictions, then it is to form the biological basiscertain of niard et al., 2006a). If this is a useful is a useful this If niard al., et 2006a). se within the NAcc has long within has se been the NAcc to perform the “teaching signal” d. ntive cues reaches the NAcc ntal events ( predict) such (Schultz events et teaching signal”, involvedin derstanding the mechanisms mechanisms the derstanding stem, butstem, one whichfor DA e of food), but this pulse pulse this but food), ofe e.g . a dinner gong) tegration of tegration th that that th via

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This In principle, GABA Irrespective, the modulatory effects of onDA the glutamater To a considerable stri extent, Firstly, within the striatum, MSNs receive twoFirstly,within of types GAB receive thestriatum, MSNs dorsal striatum exhibit do this not challenged by the demonstrationoutputs inthat, mice, from v toprojecting theVTA (indirect pathway). this [Note, str pallidum humans), in to they inhibitwhere a further serve projec MSNs D2R NAcc, to the projecting bodies onto pathway), synapsing interneuronsGABAergic that themselv their output pathways: whereas D1R-MSNs project largely direc dopamine D1 or D2 receptors (D1R or D2R), fashion to thefunction expressedreceptors within this circuit Section (See 3 an output contributing to Thus behaviour. thedetermine probability of anindividual MSN firing an (Nicola et al., 2004). The integrated sum of such interac signal-to-noise the ratio for glutamatergic 2007).ac DA al., et usually inhibitory (Surmeier activated,receptor D1R and/or with D2R, acti D1- and D2-MSNs projectD1- and from NAcc D2-MSNs thus, induces DA depolarisation further been tosuggested depend upon the state of modulate ability the awake DA’s to (Mahon alet rodents 2006), al., et complexity (Kupchik of level higher directlyD2-MSNs output innervate neurons of and Grace, 1995, West and Grace, 2002, O'Donnell et al., et O'Donnell 2002, Grace, and 1995, West Grace, and hyperpolarisation when the membrane is in the hyperpolari depolarised by glutamatergic i A receptors receptors may influence the function of the basal ganglia. ganglia. basal the of nputs (up-state), but has no or mayeffect, contribute fur atal can MSNs be differentiatedas expressing either the strict anatomical segregation of D1R strict anatomical segregation via via the indirect pathway and similarly, both D1- and whenD1 receptors the local membrane is partly 2015). Although challenged by some reports challenged 2015). Although in , variants within, and manipulation of variants GABA, vation of D1R being usua D1R being of vation polarisationdendritic the MSN membrane; of cortical, amygdala and hippocampal inputs and D1R- and MSNs differ in D2R-expressing ting through D1Rs may to increasethus serve t in rodents to the ventral pallidum (external (external pallidum to the ventral in rodents t the basal ganglia, the basal thus adding a significant and Fig 5) may contribute in a complex action potential, and thus providing 1999). ing of the systemin several ways. tions across its dendritic tree will ict dichotomy has been recently Aergic inhibitory1) 5): Aergic inputs (Fig gic inputs are a function of the sed “down-state” (O'Donnell GABAergic output pathway

entral ( es inhibites neuronDA cell glutamatergic inputhas tly to the VTA (direct lly excitatory and D2R vs D2R MSNs as both as D2R MSNs i.e. NAcc) NAcc) but not ther ther A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Importantly for the consequencesImportantlyfor the of GABA al., 2008). 2008). al., de local affect willinhibition strongly lateral be bestmay suited to influence action potential generation Thus 2002). interneurons al., fast-spiking et (Tunstall suggesting that the synaptic GABA suggesting studies support a role as inputfor integratorsMSNs over inhibitory acti net shunting yield a invariably activation of an sustained whereas role, GABAergicsynaptic inputs are clearly best suited Alternatively, the shunting rise give actions will of GABA (Plenz ms; (~50-60 frame time an appropriate within signal facilitateaction if temp potential generation under particular circumstances, Thus, 2014). somatic from the fast-spiking interneurons is consider Wils 2002, al., et (Tunstall MSNs neighbouring 450 about collaterals from neighbouring with MSNs, indi and 2) a lateral inhibitory input largely loca MSN each targeting the somata of connections 100 approximately fast-spiking the (parvalbumin-expressing) interneurons a feed-forward inhibitory pathway a rangefrom of GABAergic to increaseto or decrease, outwards and therefore depolarising (Czubayko and Plenz, 2 and Plenz, (Czubayko and therefore depolarising outwards negative membrane potential (Vm) (approximat potential for Cl associate with micromolar concentrations of DA concentrations of andDA primarilytarget ex of neurons, DA pattern phasic as tonic firing would give al.,et 2007). Furthermore, the overall GABAer and hippocamp cortical glutamatergic of window vs. dendritic location, and because of the - , meaning the net meaning , the Cl via respecti D1R or D2R activation A - R activation may fine tune the modulatory action of DA movement through GABA A R activation, at rest MSNs exhibitMSNs a R activation, at rest significantly ndritic includingprocesses plasticity (Tepper et orally coupled with an incomingglutamatergic on (Song et al., 2011). Interestingly, modelling modelling Interestingly, al.,et 2011). on (Song ted on the dendritic tree, through recurrent trasynaptic sites, whereas burst trasynaptic firing would burst whereas sites, ably both stronger, because of the proximal vidual MSNs thought to receive MSNs thought to receive vidual inputs from extrasynaptic GABAergicconductance will a GABAergic signal can be excitatory, and be excitatory, can and signal a GABAergic gic effect maybe dependent on the firing and would be restricted largely to synapticbe restricted and would ely -85-90 -85-90 ely mV), which is to serve a potentially facilitating excitatory al (Braccial inputs Moyer and 2006, Panzeri, high degree of synchronization amongstsynchronization of high degree the feed-forward inhibitory pathway pathway inhibitory the feed-forward to a net inhibitory effect. Transient, provide the strongest inputprovide the with strongest on, 2007). Of the two inputs, that inputs, two the Of 2007). on, , 2003, Bracci and Panzeri, 2006). and 2006). Panzeri, Bracci 2003, , at the soma. On the hand,other 002, Plenz, 2003, Maguire et al., al., et Maguire 2003, Plenz, 002, vely, thetemporal integration a time a windowtime of ms, 40-60 interneurons, amongst which A R-associatedchannels will be rise to low nanomolar (Koos and Tepper, 1999); and 1999); Tepper, (Koos below the reversal reversal the below Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This A secondA means whereby may GABA influence the mesolim Although it is established that a variety variety of GABA Although it is establisheda that much known is regarding the receptor stoichiometry of G regulate GABAergic transmission within striatal typeswith both receptor DA et al., engenders 1999) (Wong ( F i g 3 ) .GABAergic regulation of the VTA cell bodies of I n t h i s c a s e , pathologically relevant will require additional experimental conditions and modalities under whichsuch in inputsof supports ones. the weaker at the expense stronger reciprocal fashion me to provide the filtering detected (Maguire et al., 2014). Thus, and DAGABA inmay to their dendritic regions where high levels of re for somatic here described to those mechanisms similar locations. as yet Although lack level of acts to DA), an brake mayreceptors under some circumstances ( MSNs (Maguire al., et suggesting po 2014), a by amphetamine) greatly enhanced GABAergic tonic inhibition,acute the activation of D1 rece butWT, not from selective positive allosteric modulator, greatly increased both the selective as MSNs NAcc of 2007) al., et Floresco Wightman, 2004, and (Phillips locations synaptic inhibitionsynaptic of MSNs is bymediated from each other.However,our electrophysiological studi feed-forwardand lateral inhibitory inhibitory Extrasynaptic inhibitionmediated by . . Lastly, of the presence both D1Ron and the presynaptic D2R knockout or knockout α 1-GABA e x c e s s i v e e x c i t a t o r y t o n e a t ing ing experimental itevidence, is tempting to thatspeculate A α Rs may play a predominant role (Tan et al., 2010) in in role (Tan 2010) et al., a predominant play may Rs 4 knockout mice (Maguire et et (Maguire mice knockout 4 α 4 β -GABA GABA e.g. projections, and whether/how may they differ chanism, canonically attributed to DA, which attributed to DA, canonically chanism, tential mechanism mechanism DA whereby tential acting at D1 α (both dorsal and ventral) circuits5). Fig (see ptors (by a selective D1 agonist or indirectly indirectly or agonist D1 selective a (by ptors A neuronsDA projecting to ventral striatum during burst firing mode resulting in high tonic inhibition in D1R-MSNs but not D2R- receptor agonist receptor gaboxadol, and DS2, a 2- 2- GABA A α A receptorsis also prominent thesoma in 2 but2 also R is subunits in expressed striatum, not teraction will be physiologically and the tonic current of all MSNs from A 2003, Arbuthnott and Wickens, Arbuthnott 2003, ABA gulation of MSNs, may also apply also may apply of MSNs, gulation receptors (Dixon et al., 2010). 2010). al., et (Dixon receptors evidence. es suggestes thatperhaps of 30% A detailedA understandingof the somatic or,somatic possibly, dendritic A α receptors responsive to the the ability to strategically abilityto strategically the 4 and and 4 al., 2014). Coupling DA and al., 2014). CouplingDA teract in teract a dynamic and bic is pathway, DA the varicosities of MSNs subunits, alsoare

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This A A major is task now to integrate this emergent in the st synapses VTA from release GABA Lastly,

striatum intounderstandingstriatum our the of role ofGABA (Trigo et al., 2008). In keeping with this possibility, possibility, with keeping this In al.,et 2008). (Trigo important role in determining final outputs (Brown et al., 2 al., et outputs (Brown final important role determining in influenceMSN over that control so activity, of extensive connect Although the infew number, (TANs), that employ acetylcholine transmitter their major ( as NAcc, and for behaviour, will thus be difficult to pred difficult be thus will behaviour, for and NAcc, The outcome of such isoforms.different receptor GABAergic inputs may to VTA be function of the combined al. reducing input DA (Xiao to the NAcc et isoforms presynaptically increased input the GABAergic to circumstances, GABA Stein, 1998). However, this interpretation is su GABAergic transmission at interneurons that i GABAergic hyperpolarising GABA voltametry studies have shown that activationof GABA studies that have shown voltametry Invernizz 1992, al., et Finlay 1988, and Imperato, Chiara benzodiazepines that facilitate GABAergic inhibi (Lees it disinhibition et al., 2012). Although

motivational learning raises the possibility th possibility the raises learning motivational GABA of subtypes several of location The section. next the in possibilities these consider We allowing specificmanipulation different as of 3.2.4 Striatal GABA Striatal 3.2.4 A R agonist muscimol into the VTA significantly muscimol into the VTA increased DA R agonist A receptors conditioned and reward A receptors receptors contributemay to depola α 1-GABA A Rs may to facilitateserve transmission DA by indirect A receptors receptors in pathways known to play a role in pects ofpects motivated (and addictive) behaviour. their activity by GABAergic inputs may play an may inputs activity by GABAergic their at they may play separate roles, potentially potentially roles, separate play may at they bject to complexity further as under specific understanding of GABAergic function understandingof GABAergic in the tion decrease DA turnover in accumbens (Di 2007). Thus, the net effect of net effect facilitating the Thus, 2007). is generally observed that drugs such as drugs such that observed generally is ions of TANS may allow them considerable TANSthem allowconsiderable ions of may riatum tonically will in nhibit the DA cells. Thus, facilitation of complex interactions for projections DA to A ict. ict. receptors inaddictive processes. muscimol acting at muscimol acting A Rs by direct administration of the 012). 012). risation at presynaptic locations risation at locations presynaptic i et al., 1991), fast-scan cyclic fast-scancyclic 1991), al., i et but also co-release glutamate).but also co-release the VTA, thus potentially the VTA, or selective activation of release (Xi in and the NAcc activate interneuronsactivate α 4 β receptor Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

In a less-well definedrewardle of measure ac in deficits above, outlined As Only a limited number of studies appear toinvestigate have alpha1 3.2.4.1 reward-related behaviour. motivation thoughsimilar models, in subunit in the dorsal striatum (but amygdala or hippnot PFC, colleaguesselective have a revealed transient down regu hyperlocomotion in the psychostimulants cocain despite 2003a) conditioned (CPP) place preference was unaltered in the unawarestudies of investigating the role of other GABA 201 al., (Butkovichareas et in these lesions ofeffects various discrete depletions of the which required to particularobtain are responses et al., 2013)). 2013)). al., et with subsequent pharmacological manipulations of selective historyto differenttype of exposure of addictive drugs formation of reward-environment associations study role an important highlights for to prevent methamphetamine-induced CPP format of the striatum administration selective GABA conditioned to the place did not show such changes. These conditioned to methamphetamine; in control which drugrats A receptors in receptors the formation of drug reward α 1knockout mice. Intriguingly, using a CPPrat model, Jiao tion-outcomeassociation learning ( α 1 subunit1 in consistent prefrontal cortex, with known these wouldextremely be valuable. α α 1- GABA 1- 1-GABA e and d-amphetamine failing to induce failing ande d-amphetamine arning, the abilityarning, of cocaine to support . Yet, it remains to be addressedit remains how . Yet, a A A memory intra-(dorsal) in agreement, and, specific rewards) are found in mice with r e c e p t o r s i n t h e d o r s a l s t r i a t u m i n t h e R PAM, zolpidemR PAM, beforepairing was able ional.,(Jiao et 2016). Collectively,the e.g. 5, Swanson et al., 2015). We are are We 2015). Swanson al., et 5, A A α receptor subtypes on reward and 1 knockout mice (Reynolds et al., al., et (Reynolds mice knockout 1 opiates rolefindings a for suggest lation of the GABA d therole of d A ocampus) of rats place- vs. administration was notadministration was R isoforms (see (Shinday (Shinday (see isoforms R i.e., cocaine, may interact the ability to learn to learn the ability α 1 (but1 not α 1 subunits in subunits 1 and and α α 2) 1- Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This

effect on conditioned reinforc on conditioned effect contrast to the effects manipu of DA and it (Kelley De facilitate neurotransmission disrupt the behaviour striatum conditioned reinforcement, and again,manipula consequence having pairedbeen availability. Thwith food thearbitrarydelivery). Thus cue has acquired reinfor learn anarbitrary instrumental response that Once animals have learned the association between the cue Since DA projections to ventral striatum their influe exert alpha2 3.2.4.2 MSN MSN excitability, appearnotinto the “teaching play a role si receptors incorporating the That animals readily learn that arbitrary envi of GABA of In cont 2002). (Parkinson al., et training discriminated approach of regardless whether th leadingNAcc, to approximately 80% reductions in tissue DA with In keeping tracking). the teaching signal 2010), strongly suggesting that th that suggesting strongly 2010), functions ascribedby be affected to may DA functions with major GABAergic projection neurons, the it light onset,waiting for without food (so-called delivery rod hungry a receptacle, into delivered is food before function mentioned above. Thus, if an arbitrary stim light conditioning, the ofand forms basis Pavlovian forthcoming availability of food, their and adapt behaviour A receptors show no impairment in acquiring discrimin α 2 subunit,2 their important despite contribution to decreasing ement (Dixonement Duka et GAB al.,et 2010, al., 2015). Thus, (Beninger and Phillips, 1980) while drugs that facilitate that facilitate drugs while and(Beninger 1980) Phillips, ese receptors are not involved in motivational learning. ese learning. not are involvedreceptors in motivational lations, constitutive deletion of deletion lations, constitutive rast, mice with constitutive knockout of with mice constitutive knockout rast, modulating striatal GABAergicmodulating receptors. striatal hypothesis, 6-hydroxydopamine lesions of the ronmental stimuli can be used to predict the lfs, 1991a, Kelley and Delfs, 1991b). Again in Again 1991b). and Delfs, Kelley 1991a, lfs, theactivates cue (without activating food is worth considering what aspects of those of what aspects those is worth considering of the“teaching signal” hypothesis of DA tions that interrupt function DA in ventral e e lesion is priormade or subsequentto, to ents soon approach the receptacle at at receptacle the approach soon ents cing properties of its own as a own properties of its cing as discriminated approach,discriminated or goal nce onnce behaviour by interacting ulus (cue) is illuminated shortly accordingly, is classicaccordingly,a example is is phenomenonis is known as gnal” aspects of receptorDA and food delivery, they will ated ated approach (Dixon et al., , profoundly impair α 2 receptors has receptors2 no has α 2 subunits2 DA DA A A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This (Duka et al., 2015) fail to fail increase to 2015) (Duka al., et obtain conditioned reinforcers, but e both cocaine (Dixon psychostimulant mentioned, already as of DA; receptors are important, the effectiveness of constitutive knockout mice do not inform not do mice constitutive knockout were attributablewere to when was the infused intodrug the ventral striatum, sugg the stimulant ef Importantly, to co showing cross-sensitisation right, such sensitisation facilitated the stimulant effects of cocaine, an GABA role for In with keeping a In contrast, or (Dixon al., et 2014), or cocaine inmice learning an operant response to obtain the deletionon reward-associated learning, et 2010) al., (Stephens be complex CPP can experiments in shows no impairment r “conditioned of measure another Furthermore, function. suggests that not only are that not only are suggests 2006). and Merrer Stephens, (Parkinson et incentive learning facilitating andbehaviours, both phenomena hypothesized are to contrib behavioural sensitisation may an interactionreflect of psych psychostimulant-facili Both 2008). al., et th of administration to repeated sensitisation behavioural ability to increase locomotor activity in in locomotor activity increase to ability conditionedreinforcers. related Perhaps to A receptors, achieved using Ro α 2-GABA A receptors seemsan important to play role in the energisi α 2-GABA α α 2 knockout2 2 subunits in behavioural sensitisation, selective activationselective in behavioural sensitisation, subunits 2 α 2-GABA fects of Ro 15-4513 inthe (Dixon et alcohol al., 2012). A receptors in receptors in this region.experiments While the lever pressing, or nose-poking by by nose-poking or pressing, lever A receptors appropriately receptors located in ventral striatum to

mice (Dixon et al., 2010). Although interpretation of of interpretation Although al.,et 2010). (Dixon mice 15-4513's agonist agonist 15-4513's us regarding us precise the area in which α al., 1999, Robinson and Berridge, 1993, Le Le 1993, Berridge, and Robinson 1999, al., 2 knockout mice, they do not give rise to rise dothey not give mice, knockout 2 tation of conditioned reinforcement and reinforcement and conditioned of tation d induced behavioural sensitisation in its own α this, while psychostimulants show a normal whilethis, food (Dixon et al., 2014, Dixon et al., 2012), Dixon al., et 2014, al., et food 2012), (Dixon 2 knockout2 drugs facilitatedrugs instrumental responding to drug injection into striatum the ventral , in keeping with a lack of effects of with keeping a lack of in effects , e drug (Dixon et al., 2010, Morris Morris 2010, al., (Dixon et drug e t al., 2010) and methylphenidate methylphenidate t al., and 2010) α esting strongly that effects these

properties in in properties animals do not differ from do animals WT 2(H101R) were mice also seen eward”, CPP to cocaine, also also to cocaine, CPP eward”, caine caine (Morris et 2008). al., ostimulants ostimulants with conditioned ute to drug abuseby α 2 knockout2 α 2(H101R) mice, ng aspects α

mice for for mice 2-GABA of α 2- A

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This α conditioned by ps drug-seeking That these observationsThat from resulted Similar to the constitutive alpha4 3.2.4.3 may functions inwhether D1 distinct they serve consequences of cocaine. Thus, influence addiction-related behaviours,their reinforcers reinforcers in WT (but not though this treatment reduced cocaine potentiation of respond gaboxadol, into the NAcc, no effect on respo α4βδ toserve inhibit motivationobtain co to that toni (Macpherson suggesting al., et 2016), littermates in learning to approach the food level of responding in the responding oflevel both Similarly, 2016). (Macpherson al., et elicit presentation of the cues the cues presentation of elicit contrast to conditioned reinforcement. However, in comp by infusion of an Ad-sh control and directly into ventral striatum (Macpherson alet food-predictive properties of the CS+. Similarly, the showed increased instrumental responding for the conditio responding for the conditioned reinforcer equa of cocaine dose Administration reinforcer. responding, were they suggesting more hi 4-GABA receptors ofreceptors were WT mice activated by local infusion o A receptors (see (see receptors below). section 3.2.4.3 α α 2 knockout 2 4-subunit viral knockdown demonsviral 4-subunit mice α 4 adenovirus,4 scrambled se but not an adenovirus a carrying

mice), mice), α α 4 α 2

knockoutmice). mice). knockout- 4 knockout mice, mice, knockout

knockout ychostimulant although it at present is not known drugs α α 4-knockout displayed mice higher levels of instrument 2-GABA via nose-poke demonstratingthus responding, robust α 4 deletion specifically in ventral striatum was shown striatum was ventral specifically in deletion 4

mice being maintained across the cocaine doses A α receptors may be involved in the facilitation of of involved in may the facilitation be receptors chamber following the onset of a predictive cue predictive cue of a onset followingchamber the 4 knockout 4 nding for the conditioned seen, was reinforcer α ghly to obtain motivated the conditioned c GABAergic inhibition of MSNs may normally may inhibition GABAergic c of MSNs nditioned reinforcement. However, when 4 knockout 4 ., 2016); as with constitutive knockout mice, knockout as mice, with ., 2016); constitutive manipulation influenc manipulation

vs lly the heightenedboth across genotypes, arison to their WT counterparts (and in arison to (and in their WT counterparts -dependently potentiated instrumental-dependently potentiated D2 MSNs as appears to be the case for

trated an equaltrated the ability to learn and WT mice accurately learned to α 4-subunit viral knockdown mice

mice do not differ from their WT WT from their differ do not mice f the ned reinforcers relative to α4βδ ing for conditioned es the motivationales -preferring agonist, quence, quence, al Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This These dataThese suggest some similarities, an

administered systemically, or directly into the NAcc of W administered of NAcc systemically, or directly into the cocaine-CPP (Maguire facilitated Howev 2014). al., et expression (Maguire of cocaine-CPP Like ofFinally, the deletion specific enhance CPP. In contrast, enhance CPP.In contrast, knockout

GABA subunit deletion, suppression of deletion was limited was to D2R-expre deletion responding for the conditioned reinforcer. Since simi of cocaine to increase responding; th instead, involved in the prediction error/teaching sign predictionerror/teaching involved in the α gaboxadolof cocaine-potentiated attenuation the constitutive CR knockout, potentiating impairing transmission at responding for a conditioned reinforcer and mediated knockdown (Rewal et al., 2012). al., (Rewal et knockdown 2012). mediated conventional while reinforcers, responding 2012) al., et (Rewal rats in knockdown viral by or 2016) mice),butnot from D1R-expressing cells ( controls, providing that evidence further for the conditioned reinforcer. mediatedD1-MSNs notinhibition was involv of are involved in mediatingre involvedare instrumental learn the associationbetween reward, sugge the CS and food 4-GABA α A A 2 receptors.neither subtype Deletion had of

knockout mice, constitutive knockout constitutive mice,

A receptor-mediated inhibition receptor-mediated of D2R-ex mice, blockedmice, the ability of cocaine, ad α 4-GABAARs in4-GABAARs constitutive α 4 D2 α α et al., 2014). Furthermore, the Furthermore, 2014). et al., knockout 4-subunit D2R-expressing from DA cells ( 4 subunit expression had no expression consequences subunit 4 for the abili ssingappears neurons,that it α 4 d somedifferences functionsthe in of sponding for reward-conditioned cues.

knockout mice did not differ from WT in theirnot miceknockout differ from WT in did α α - 4 4-GABA D1 mice exhibited normal cocaine but CPP, no al function of the striatum. However, unlike However, striatum. the al function of for alcohol was decreased following virally- f responding and blocking intra-accumbal CRf responding. These data demonstrate that knockoutmice), mimicked the phenotype of e deletion was itself sufficient to was itselffacilitate sufficient deletion e ed in determining ed of the strength response its potentiation by cocaine. Importantly, its potentiationImportantly, cocaine. by consequences the animal’s for ability to A pressing neurons reduces instrumental neurons instrumental pressing reduces receptors specifically within the within the NAcc specifically receptors ministered during phase, the test to α 4 knockout4 (Macphersonmice al., et lar wereeffects found when the T, but not T, er er did not affect responding for for responding affect did not α sting that 4 D1 α4βδ knockout mice showed showed mice knockout α α agonist, gaboxadol, 4 4-GABA

α knockout or or knockout 4, like like 4, α 4 D2 α A A 4 and4 α receptor- knockout knockout 2, is not is not 2, α α 4 α 2- ty ty D1 2 2 Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Determining the role of GABA GABAergic Integrating 3.2.5 psychostimulants and thereby influence their ability to po MSNs provides intrinsican mechanism to differenti In conclusion, interactions between DA and GABAergic ton behaviour, while similar inhibition tonic inhibition of to weakenD1R-MSNs serves Nevertheless, collectively, observations these suggest that indirect output pathwaysvalidtonobelonger for the m report the recent the demonstrating segregation of D1R D2 and (Maguire enhancement et 2014) al., function is competitive in but nature, also function window inhibition. for This proposal is consistent with desynch because possibly desynchronised, themselves, feed-forward would be most inhibition when effective fas targeting inhibition of the non-synchronised significant increase in inputs. Feed-forward in way, lateral inhibition th could also constrain coordinated inputs, by silencingthe activity of to confer timing inof precision the the response neur the perspective, modelling From the al.,et 2014). i lateral roles ofputative of the understanding very recent such a investigation, utilising of attempts beenhave tomade model how thes connections, and the individual conductances at knowledge because of inputs.the However, s gainedfrom the ensemblesaccess of the complex striatal challenging because the currently available ex molecularand dysfunctio behavioural reward-related A A receptor-mediated signalling in the striatum has proved of D2R-MSNs has little effect. . These findings complex, are modelling approach has resulted in a better a better modellingresulted in approach has reveals the importancereveals of the latency of the , , the synchronisedover MSNs. Intriguingly, those MSNs notthat are synchronised. In this e e of the networkgain when even is a there nhibition and feed-forwardnhibition inhibition(Moyer the ability of cocaine to facilitate motivated the ability of cocaine to facilitate motivated network and their response to the cortical their response and network hibition would bytask aid specificallythis perimental approaches cannot adequately e factors interact may at a network level. A the single the single ancell level, increasing number specific task of lateral inhibition of task specific would be ally affect their excita ronised firing would afford a larger a larger afford would firing ronised tentiate conditioned reward. the long-held view that striatal ouse NAcc (Kupchikouse 2015).NAcc al.,et ic inhibition of D1R- and D2R- tudies oftudies both the anatomical onal ensembles onal ensembles to incoming α 4-GABA t-spiking interneurons are, t-spiking are, interneurons R to the direct and MSNs particularly in the light of A receptor-mediated bility in response tobility in response ns ns Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Addictive behaviours might then result from 4.1. Altered subjective effects of drugs Altered4.1. subjective genetic and human the animal studies 4. Integrating inputs (asinputs expectedwith a loss of defi a framework, In this prioritised. being ensembles (Maguire et al., 2014). Our comparative findings with mice (Maguire Our findings et comparative al., 2014). in D1R- or D2R-MSNs or both neuronalor sugges populations, both D2R-MSNs in D1R- or being active simultaneously. efficient shift between different actions, while also pre forwardwould inhibition facilitate both se associating the actionoutcome with itsrepresentation choice behavioural perspective. Thus,lateral inhibition with spiking would interneurons endow network the striatal ensemble “winner”of the competition.The c ensembles responsesof (ratherthan the ensemble the size predict as as predict impact feed-forward inhibitory inputs; however, th ensembles. On the other hand, a deficit in ensembles.hand,a deficit other Onthe would conceivably the gain alter of the stri D1R+ve MSN-mediated tonic inhibition ac inhibition tonic MSN-mediated D1R+ve mediatedeffect of feed-forward depende inhibition be may associated with a psychostimulant (M with a psychostimulant associated consequences may similarly apply to late and behavioural outcomes. similar A dichotomy albeit with D1R- or D2R-MSNs maybe activated byspecific cortical inp tempting to speculate that distinct fast-spi inhibition would appear to control motivation by chronic drug intake are warranted in the near future. future. near the in warranted are intake drug by chronic exploring su Studies to be elucidated. remains α 4-GABA A Rs are expressed on both fast-spiking interneurons and th α 2-GABA aguire et al., 2014). Yet, D2R-MSN D2R-MSN Yet, 2014). al., et aguire ral inhibitionwherethe role of D1R α 4-GABA ts to oppose an excessive tone, DA king interneuron populations targeting either ooperation between between ooperation lateral inhibitory and fast- A A lectionmost of the appropriate action and ch possibilities and how may they affected be receptor signalsin the of dendrites MSNs), would improve learning would improve actiona new and of atal outputtheatal MSN and bias output of increased probability of “addictive action” to obtain to obtain the reinforcing stimuli. It is e net effecte of such deletion is difficult to A A receptor-mediated tonic inhibitionmay

cit in inhibition from lateral inhibitory inhibitory lateral from inhibition in cit

venting venting competing actions from selectively lacking the ntonneuronalMSN type, the as a number of advantages froma a numberadvantages of t that the uts to elicit defined functional possibly possibly different behavioural s) inestablishing s) MSN the . On the other hand, feed- α 4-GABA e target target e MSNs vs vs α 4-mediated 4-mediated A D2R-MSNs D2R-MSNs receptor- α 4 signal signal 4 e.g. as Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This the GABRA2 gene. the GABRA2 Somegene. support for this interpretation c / expressiregion that changes the stability a tag but does not the proteinchange sequence. This and other creates SNP 2008). The rs299858 a inchange the associating risk variants with changed processing consistent with reduced inhibition of accumbe al., 2014), et GABRA2 of(Heitzeg rs279858 allele G risk in is enhanced anticipation reward during activation NAcc inreceptors brain, the andthrough this Integrating data fromanimalhuman and is hiexperiments often animal findings with geneti subunits, might such risk variants behaviouralhave effect carr (risk allele) allele rs279858*C that 2015) al., et (Lieberman showing high density of humans translateinto for addictions risk are notundersto by which mechanisms The variat neurobiological human gene-variants conferring increased humanconferring gene-variants by psychostimulants.Neveofto facilitation reward-seeking s reward control over to contribute to thought but al., 2010), by (Dixon et about 30% (MSNs) inhibitory phasic GABAergic reduces only As discussed above, deletion of discussed As deletion above, and BerridgRobinsonaddiction (Robbins and2007, Everitt, and with reward associated area a brain 2000), conditioned reinforcer inmicewith ability of the psychostimulant, methylphenidate, a human version conditioned of the mouse reinforcement te different inexperimental measures the two sp α 2-GABA c deletion of the subunit? deletionc of the subunit? α α 2 mRNA is lower in neural cell lower cell cultures derived in is neural from mRNA 2 2-GABA A iers. If risk variants of GA variants iers. If risk receptors in the NAcc (Dixon in the NAcc et receptors α 2 subunit2 deletion, and humans α mechanism affect incentive learning. 2 subunit expression is inconclusive subunit2 is expression (Haughey et al., A receptors in the mouse receptors ( risk for addictionof expression alter currents incurrents accumbal medium spiny neurons ecies (Stephens et al., 2010). However, using (Stephensecies 2010).However, al., et motivation and implicated in drug abuse and in drug abuse implicated and motivation eeking (Dixon et al., 2010), and in particular eeking and 2010), in et al., particular (Dixon on of the mRNA and thus alter alter expression of on and of thus the mRNA also leads to altered function of systems systems leads tofunction altered of also to instrumental facilitate responding for a ions in non-coding regions of GABRA2 in triplet codon for amino acid residue 132, 132, residue acid for amino codon triplet suggesting an effect on incentive on an incentive effect suggesting e, 1993) provide a potential clue. a potential provide 1993) e, human adolescents carrying the carrying human adolescents intronic in SNPs the vicinity may rtheless, it unknownwhether is od. Clearly, the rodentClearly, od. studies ns MSNs, but direct evidence s ins humans that parallel the BRA2 reduce expression of of BRA2 expression reduce st, we we st, foundin similarities the omes fromomes a recent report al., 2010, Pirker et al., al., et Pirker 2010, al., carrying risk for alleles carrying α ndered by the use of 2

knockout mice) not α 2-GABA α 2 2 A

Interestingly, in addition to loss of the abi of the inInterestingly, addition to loss Furthermore, comparedFurthermore, to subjects, heterozygous subjects proving) a lowered levelof a lowered proving) neuronal cell cultures derived from the corres Although this SNP differs from those thisused inAlthough most differs SNP from those studie one of th as in homozygosity rs279871 SNP of cocaine addiction (Duka al., et 2015). In our ex may be linked to not only alcohol rewardand alcohol-rel anticipation, the insula with activationreward in suggesting that enriched for alcoholism, (Kareken area tegmental ventral in the response areasin anfMRI study;contrast, the heterozygous in subje an increased response displayed at rs279871 allele common alle for the homozygous individuals lower had rs279836 and rs279828 rs279826, rs279845, of carriers keeping, In rs279858. of allele importance that SNP rs279858 is is rs279858 SNP importance that may area alone be driv in this genomic variations during anti reward impulsivity and 2006b) al., as (Enoch al., et 2010), and cocaine abuse 2005) al et (Covault populations of addicted studies linkage disequilibriumwith the rs279858, comm (Johnson Project from the 1000 Genomes in measures of positivemeasuresin such affect of as stimulat found subjective previous2014) studies decreased al., et 2005, and “arousal”. (Pierucci-Lagha Other responses to the specificallydrug, in rating reinforcement in the “risk”genotype,we alsofound mark GABRA α2 -GABA 2

polymorphisms found were linked to to be increased A associated with a reduced reduced with a associated receptors in rs279858 risk-allele carriers. carriers. risk-allele rs279858 in receptors the minor alleles for SNPs rs279858, rs279844, for SNPs rs279844, minor rs279858, alleles the lity of methylphenidate to lity of facilitate methylphenidate conditioned le at each SNP (Uha SNP each at le s of drug-induceds “stimulated” “restlessness”, et al., 2008) shows rs279871 to be in to 100% be in rs279871 shows 2008) et al., ion, vigour andin happiness, ofcarriers the C- ., 2004, Fehr et al., 2006, Lappalainen et al., al., et Lappalainen 2006, Fehr ., al., et 2004, periment, we used we possessionperiment, of allele G the ponding risk allele, consistent with (but not not (but with consistent allele, risk ponding e identifiers of a genetic “risk” population. of“risk” a genetic population. identifiers e well as childhood conduct disorder (Dick et disorder (Dick et conduct childhood well as ing our genotype differences. It is of thus cipation (Villafuerte et al., 2012). Thus 2012). Thus al., (Villafuerte et cipation et al., 2010). Finally, in a family sample in al., et 2010).Finally, family sample a Roh et al., 2011), but not all (Arias et al., on recognised SNP risk across multiple to alcohol-associated effects ofofeffects another abuse, alcohol, drug 'N s of s egative' alcohol effect scores than scores effect alcoholegative' ed changes in their ed changes subjective GABRA homozygousfor the high-risk atedcues, but to a general rt et al., 2013). 2013). al., et rt cts an displayed increased α GABRA 2 2 mRNA expression in 2, SNAP analysis of data analysis SNAP of data 2, cues in medial PFC PFC in medial cues 2

Such changes in reward-related behaviours precedemay the effects Personality 4.2 Taken together, these studies may sugg be be mediated by personality charac decreased likelihood and of an marrying, increa development of alcohol dependence, the high-risk status; while both betw relationship the of provided by a study is interaction factors leading to alcohol at a la dependence may impulsivity like characteristics or personality reward between associations Thus 2006b). al., et (Dick consistently apparent until but the mid-20s, dependence. An elevation in fo the risk 2012). al., et Villafuerte dysfunction of the reward system in alcohol-de theft,and vandalism) influenced that are neverthelessdevelopmentassociated with the primarilythandelinquent alcoholfor behaviour rather abus to “externalizing behaviours” as and include aggression and whichdisorders alcohol abus includes and drug r may control such in Impairments to reward. sensitivity in personality characteristicwith deficits is the the relationships between monitoring, and adaptive (Trucco both adverse et (GG, minor allele with GABRA2 adolescents in rs279858) and rs279826 (rs279827, variants influenced by parental monitoring.Recently, the Michigan negative consequences in adulthood, but also adolescent of association the shown have studies Several GABRA2 GABRA2 and marital status contributed marital status and independently to the teristics (Dick et al., 2006a). 2006a). al., et (Dick teristics variants and parental monitoring influences to seem be r alcoholr dependence associated with est thatest the primary association of s associated with behavioural control and with by both and genetic environmental factors. then remains constant throughout adulthood how externalising behaviourhow is adolescents in externalising rs279827) are most susceptible to parental to most susceptible are parental rs279827) ter One stage. example of such a potential e. Such impairments are sometimes referred sed likelihood of divorce, whichsed likelihood appearsof to pendent(Villafuerteal., subjects 2013, et GABRA al., 2016a, Trucco et al., 2016b). Although Although 2016b). Trucco al., et 2016a, al., of problematic alcohol of problematic and drug use, if adolescents were able to show that to show that were able adolescents GABRA2 2 risk haplotypes and haplotypes risk 2 sensitivity to een een eveal themselves in a variety of of a variety in themselves eveal e, e, interact with environmental environmental with interact externalizing behaviour with with behaviour externalizing (rule breaking variant is associated variant a with per se per GABRA2 group development of alcohol , the same variants are are variants the same , , examining genotype and family GABRA GABRA2 e.g., defiance, 2 variants variants 2 GABRA2 is not

Regarding rewardsensitivity as a factor infl Such developmental may trajectories be the reason for apparen present the externalising behaviour was found to be less externalising behaviour was influenced bypare The association al., 2004). of et dependence (Edenberg associat previously that was found (rs279858), behavi persistently high externalising (Dick of age Import years al., et 2009). 22 but alsowhen declining measured in a cohort of children found to show of behaviour patterns persisting symptomatic Conduct Disorder, as well as less GABRA2 regarding and polymorphisms the presence of alc problematic alcoholis use develops) associatedvari with persistence of delinquent behaviour from early adolesce delinquent behaviour is in present mid-adol integrate these kinds ofa systematic observation into account.kindsthese integrate co of such receptors behavioural in involvement dependent on to that the of benzodiazepines evidence ability is conduct disorder deficits in individuals risk psychostimulant effects on control over rewa and individuals o of Our findings. allowintegration to an studies, animal thoughdirectly comparable measures have the animal literature, impaired control reward-seeki over (Dick et al., 2009). 2009). (Dick al., et α 2-containing receptors (Newman et al., 2015) is perhaps su is 2015) (Newman al., receptors et 2-containing α 2 knockout mice (Duka et al., 2015) point to commonalitie point to 2015) al., et (Duka mice knockout 2 our were more likely to carry thecarry likely to more were our uencing addictive behaviour, and returning to been seldom been outcarried in both human and escence (Trucco et al., 2014). Furthermore, Furthermore, 2014). al., (Trucco et escence severe behaviourssevere of delinquency, been have rd seeking, butrd seeking, how relatethese to human at present at present Similarly, for surmise. a matter antly, the individuals showing patterns of from adolescence adulthood, to young early ntal monitoring;ntal if parental monitoring was promote aggressive behaviour in mice is in is mice behaviour promoteaggressive ed with increased risk for adult alcohol alcohol ed with for increased risk adult ntrol. However, thereHowever, is much ntrol.to do to persistent. ants in the ants followed from 11 of age years to nce to young adulthood (when ng be may a common feature, wn studies in GABRA2 “risk” in GABRA2 “risk” studies wn

ohol dependence. Clinically GABRA2 tly contradictory findings GABRA2 with persistent persistent with GABRA2 GABRA2 SNP (rs279858) (rs279858) SNP ggestive of ggestive variant variant s in s Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Moreover, Amongst higher order dysfunctions higher contributingAmongst to 4.2.1 GABA 4.2.1 reversed by pharmacological manipulation of consumption exposed by adults exhibited rats has also been suggested bothin animals; significantrole. Variations inGABA behavioural factors. A relationship between between relationship A factors. behavioural impulsivity, with the remaining being75% accounted by o SNPsassociat suggestsof the that about 25% analysis bootstrap A 2013). (Villafuerte al., et with and of four impulsivity these, with also associate Life behaviour (Dick et al., 2013). As many as 11 SNPs with SNPs 11 as many As 2013). (Dick al., behaviour et clinical disorders characterised by a lack conof impulse oftraits, behaviourala significant lin workhas body of Although impulsivity 2013). al., et Villafuerte misuse alcohol) (and especially to drug related influence GABA investigations should exploreidentifother impact of the 201 al., et (Caprioli rats impulsive for highly reported and contentin GABA the anterior cingulate cortex andNAcc drugmisuse mediatedby variation in the evidence for overlapping neuronal mechanisms and substr activation in both (Villafuerte andinsula NAcc (Gondre-Lewis et al., al., et (Gondre-Lewis with reduced a recent study highlighted earlier, though, as (Silveri et al., 2013) is of interest. Simi of interest. is (Silveri al., et 2013) selectivereduction in the GABA signal in the observation that in humans high oflevels A GABRA2 receptor and impulsivity: an addiction-relevant re addiction-relevant an receptor impulsivity: and α 2mRNA in an iPSC culture model (Lieberman et al, 2015). al, 2015). et (Lieberman model culture iPSC an in 2mRNA A receptor function at selective neuronal loci remains an SNPs associated with impulsivity associated with impulsivity SNPs 2016)- see section 4.3). 4.3). section see 2016)- A receptors play a significant role in impulsivity traits intraits role impulsivity receptors play a significant larly, in animals, animals, in larly, is a complex construct encompassing a number encompassing a construct complex a is indicates indicates a specific SNP, to associate rs279858 the increased impulsivity and high alcohol α impulsivity in adolescents associate with a with a associate impulsivity in adolescents α et al.,et 2012), thus providing some anatomical probing for a causal for 4 these relationship a causal probing for α 2 and2 impulsivity and alcohol consumption 2 gene. How these genetic variants may may How gene. 2 variants genetic these anterior cingulate cortexsubjects of adult (Dick et al., 2010, Villafuerte et al., 2012, (Dick al.,et et 2012, Villafuerte al., 2010, ion is mediatedtheirion is by associationwith 2 GABA 2 to a paradigm of stressearly-life can be drug abuse, impulsivitytoplay appears a a decrease in GABAa decrease ked the ked in the in the associate with increased neuronal A ied function onSNPs the receptor Rs in selective neuronal locations 4, Hayes et al., 2014). Future Future 2014). al., et Hayes 4, ates betweenates impulsivity and trol, or general trol, externalising or general α core respectively, have been time Alcohol Problem Score time Alcohol Score Problem 2 2 havegene associatedbeen GABRA2 lationship? lationship? ther, yet to be identified, yet ther, gene to a variety of In this respect, the respect, In this A receptor binding open question Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This hypothesis, (Nelson et al., 2009) 2009) al., et (Nelson hypothesis, byincreasing the liferesponse to traumatic eveemotional 4.3 GABA 4.3 As already noted, for certain addictions,GABA noted, already variationsin As GABAergic at hippocampal responses GABA upon genetic polymorphisms. Exposure of receptorsensitivity,altered and sensitivity of early life exposure to traumatic events may alter GABAergic childhood trauma in increasing forrisk post-tra in is that variations possibility in response toand fearful insular activation preliminary suggests report a correlationstrong between conditione to mice of the sensitivity increases is also thismarkedly influenced2016), relationship by of predicts the development 2010). A considerable animal literature implicates implicates literature animal considerable A 2010). phenotype (Enoch et al., 2010). For example, example, For 2010). al., et phenotype (Enoch interact with childhood trauma in predisposing to the devel responses tothat cocaine resemble those in leading to impaired GABAergic inhibition of accumbal med specific reduction in adulthood of found thatexposure of to mice early life stre diminished transmission through al., 2008, Dias et al., 2005, Smith et al., 2012), whi 2012), al., et Smith al., 2005, et Dias 2008, al., 2000 al., (Low et barbiturates and benzodiazepines of actions modelling the impactof GABA in providingstudies will ofsome the star be instrumental protein (Tang al.et 2005) produce truncated a SN with impulsivity-associated the strongest A receptor gene-environmentinteractions drug dependence Messina(Enoch, et Cad 2011, 2008, drug al., A GABRA2 receptor dysfunction receptor at re reported reported that polymorphisms in α α 1GABA 2 but not but 2 may risk increase the development for addictions of A A R s ( H s u e t a l . , 2 0 0 3 ) . V e r y r e c e n t l y , w e h a v e receptors, an effect that has been attributedbeen that has to an effect receptors, α gene expression gene tosuchevents may depend 2 Ps, rs279827 close to a close to a splicing rs279827 site able to Ps, ss during postnatal to days p2a to leads p9 faces (Stein et al., 2006). 2006). al., (Stein et faces distinct one Thus, rat permanently pups to stress diminishes while experience of childhood trauma alone trauma of childhood experience while

d anxiety (Dixon et al., 2008). In humans, a a In humans, 2008). al., et (Dixon d anxiety knockout umatic stress disorder (PTSD). Alternatively, , emerging as a potential candidate. These a potential candidate. These as emerging , α 1 subunit1 instriatum,expression ventral α le genetic deletion of the le genetic 2-GABA GABRA2

mice (Lambert, 2013) . 2013) (Lambert, mice levant neuronal networks. GABRA2 GABRA2 ium spiny neurons, and altered tingpoints necessary tobegin A A , Morris et al., 2006, Dixon et et Dixon 2006, al., et Morris , receptor subunit genes may may genes subunit receptor gene expression, resulting in Rs subunits intheanxiolytic gene variantsgene (Enoch al.,et nts. In keeping with that GABRA2 opment of an addictive genotype and amygdalar interact interact with early α 2 subunit2 et, et, Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This pathways (Fig 5), also may contributeto addictive behaviour. the amygdala (Marowsky and2012) othe al., et expression of Intriguingly, a persistent down regulation of regulation down persistent a Intriguingly, been peri-pubertalreported for a paradigm stress in rats subunit expression in the amygdala and an associ abnormalities indicative of a orphysical hasstress emotional been also these findings suggestcoordinated these that a a ofCRF antialarmin, antagonist the amygdala in increase an measures, effect both behavioural Additional GABA mediatemay the effects of early-life stress on atreceptors selectivebut overlapping neuronal In the In the context of interactions between stress early-life 4.3.1 rolea Neurosteroids: involv neurocircuits in associated with a selective increase in the protein levels alcohol and bing bothimpulsive of indices in increase shownto eng has been in rats separationmaternal In keeping, Thus, consistent with a specific pattern of altered expr altered of pattern specific a with consistent Thus, subtype following subtype toearly-lifeexposure a sel stressor, inhibits inhibits of 3PBC micro-infusion amygdala.Remarkably, mPFC and the immunohistochemical analysis in the NAcc has that revealed b GABA Therefore, al., 2015). variations in the neur neur brain-derived of group by a allosterically worth that the function noting of such receptors can be end A A α receptor functionreceptor across the CNS. Our electrophysi recent 2-GABA α 3-containing and/or A A receptor isoforms also may be sensitive to environmental receptors in either locus, reversed the maternal separati depressive-like depressive-like behaviour al., et (Warren dec 2013). A receptor receptor which mediateisoforms, tonic inhibition in regulation of expression levels of regulation of reported and is accompanied andreported is by behavioural the increased risk for excessive drinking. drinking. for excessive risk increased the Gabrd osteroids (Belelli and Lambert, 2005, Gunn et Gunn 2005, et and Lambert, (Belelli osteroids onal ofon levels can impact neurosteroids r neuronal populations neuronalr motivational within (Gondre-Lewis et al., 2016). Collectively, Collectively, 2016). al., et (Gondre-Lewis also mimicked by local administration into into administration local by mimicked also loci of and the stress motivational circuits ated in increase anxious-like behaviourhas ed in addiction? in the VTA of rats exposed to chronic and GABA ectivedecrease in ession of distinct GABA distinct of ession e-like drinking behaviours, which behaviours, drinking e-like of the GABA

(Tzanoulinou al., et 2014). , a ligand that selectively selectively that a ligand , ender in adult animals an adult animalsinan ender A receptor receptor it is function, ogenously facilitated A R oth synaptic and α 2 subunit2 in the α 3 but3 not ological and influences. on-evoked A A α 2-GABA receptor reased reased α 2 2 A

neurosteroid signalling neurosteroid signalling complex, obseis the relationship the While (Ford mice female et 2015). al., gene, essential in the synthesis of allopreg et knocking al., 2015). (Ramaker Importantly, in consumption mice, when given either system the administration of the synthetic analogue Janak 1998, al., et (Janak rats by self-administration operant keeping, ofa publications foundnumber ofhave effects 20 al., et Kumar 2004, al., (Sanna et neurosteroidsactive may some mediate of its actions bymodulating the synthesi modulation of NAcc GABA via function consistent with reports previous a suggesting role for e Belelli and Lambert, glia cells (Mitchell, MSNs (DARPP-32 positive), but also DARPP-32 cel negative neurosteroids while immunoreactivity for one ne extrasynaptic GABA (Porcu and Morrow, 2014) . In that co and . In that (Porcu 2014) Morrow, necessary to clarify a GABA function.exploring studiesFuture targeted supporting a dynamicrelationship between alcohol, neuroste withdrawal seizure-prone and re synthetic enzyme expression levels ( limited. are However alcohol still consumption production andregulation its in relevant neuron Deta al. 2006). in et Morrow animals (reviewed thisadaptation suggests to contribute may in increase neurosteroid developedlevels in GABA influence the (5 alpha-r ability of finasteride A receptor active neurosteroids) active receptor decr to A inreceptors MSNs are sensitive to physiological concen A receptor-mediated role of neurosteroids in alcohol action sistant mouse lines (Tanchuck indirec thus al.,et 2009), e.g. A receptors (Frau et al., 2013). 2013). (Frau al., et receptors 5 ntext it is of interest that that that that interest of is ntext it α -reductase) are differentially altered in alcohol- unpublished). Collectively are findings these alcohol-dependent animals (Khisti al., et 2005) nanolone,ethanol increased consumption in rvation that tolerance to the alcohol-induced to the tolerance rvation that nce abuse,nce it been suggestedhas thatalcohol out the gene encoding the encoding I 5a-reductaseout the type gene , , ganaxalone, limited reduced ethanol access the the excessive alcohol eductase inhibitoreductase that decreases levels of the the role ofof a range neurosteroids are ically (Ramaker et al., 2012), or into NAcc or into 2012), NAcc al., et (Ramaker ically urosteroid, allopregnanolone, is is allopregnanolone, evident inurosteroid, al loci in rodent lines loci in rodent lines al bred for selectively ease the subjective effects of alcohol, , neurosteroid content, sensitivity and and sensitivity content, neurosteroid , iled investigations into neurosteroid into neurosteroid investigations iled ndogenous neurosteroid in the ls, presumably interneurons or allopregnanolone on ethanol 09, Morrow et al., 2006). In In 2006). al., et Morrow 09, and Michael Gill, 2003), while while 2003), Gill, Michael and between alcohol intake and and intake between alcohol s of these GABA roids and GABA consumption in such GABRA2 A trations of A receptor- receptor alleles alleles tly tly s Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This plays a crucial role in drivinga crucial plays role the increased sugges have modelling computer with combined and in studies Recent in human 2006). al., et be instructiv may associated with Parkinsonism EEG? comparisonA with understandingour current of the i

association between the the association between parents, and in individuals with a family Increased and increased EEG rs279841) rs279863, rs279871, a significant association four between months 24 of minimum In a cohortof alcohol 44 dependent patients How could an GABAergic altered signal mediated by 2014). and parent of 4,026 adolescents, twin sample Electrical activity of the brain me forbiomarker potentiala related G changes; EEG 4.4 associated with Parkinson’s disease, primarily Lagha et al., 2005). Lagha et al., 2005). abuse and dependence. dependence. and abuse such inincrease neurhas proposedbeen that because variationsFurthermore in the of the restingEEG in awake beenhave foundstrongly associated with the to be Ba 2004, al., et (Rangaswamy alcoholism suggesting that certain effectsofneurosteroids aremed power power in alcoholics (Rangaswamy et al., but 2002) dependence (Costa and 199 Bauer, Hz) has proposedbeen to 15 30 as a β power has been reported in the EEGs of the offspring the of offspring EEGs in the reported been has power GABRA2 the majority of healthy adults (Edenberg et al., 2004). al.,et (Edenberg healthy adults majority of the asured by EEG and, in particular, gene and beta gene power was confirmed in a community 7). Further studies have confirmed the increase of b increase the have confirmed studies Further 7). GABRA2 uer uer and in Variations Hesselbrock, 1993). β key endophenotype for alcohol and cocaine power. In studies, these history of alcohol dependence. Recently an s genotyped for 527,829 SNPs (Malone et al., al., et (MaloneSNPs s genotyped for 527,829 who had been abstinenta from alcohol for onal excitability would predispose to alcohol e in this respect (Goldberg et al., 2002, Costa Costa in2002, e this al.,et respect (Goldberg gene affect the level of neural excitability, it it affect excitability, of the level neural gene cause a reduction a cause inlateral inhibition that animal models of Parkinson’s disease, animal models of Parkinson’s disease, ted in that lateral a inhibitiondecrease also in individuals with family history of β α power was found (Lydall et al., 2011) 2011) al., et (Lydall found was power β ABRA2 variants? variants? ABRA2 2-GABA frequency which represents 15–20% iatedby ncreased powerncreased of A R lead to R lead an increase

GABRA2 GABRA2 β power (brain of waves α deficits in DA, typically typically in DA, deficits of alcohol dependent dependent alcohol of 2-GABA SNPs (rs548583, (rs548583, SNPs A β Rs (Pierucci- oscillations oscillations β GABRA2 power power eta eta

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Furthermore,a reduction in the (Damodar firing interneurons synchronized changes following manipulation changes of specific subtypes of unexplained. And animal while studies have id the biological link the between genetic variat provocative thatevidence certainvariants are genetic associated signals within reward pathway. human Although the genetic as interconnected areas interconnected areas intrinsic properties intrinsic properties possible that changes these may accompanied be by addition hippocampal and cortical (Buzsaki assemblies firi interneurons fast-spiking of influence strong the Investigations of the past decade Investigationsinto decade of the the of GABA role past 5. Conclusions β findings intoa broader account of addictive behaviour r these alterationsthese be sufficient may to entrain more MSNs into estimatedcharge) 30% the synaptic and combof through the reduced reduced the through couldthis in turn simi 2015), (Lieberman al., et reports appears to providedrivepowercrucialfor a increased appears the decreased by the loss of the glutamatergic signals to increase MSN firing synaptic at locations along wh MSN dendrites GABA GABA dependence have begun to the uncover complexity of the the the is Thus, it 2015). al., et Damodaran 2014, al., et oscillation. oscillation. α 2 SNPs does indeed translate SNPs 2 to GABA a reduced A A receptor function (Czubayko and Plenz, 2002, Plenz, 200 Plenz, 2002, Plenz, and function receptor (Czubayko receptor isoforms orchestrate the integr isoforms receptor orchestrate e.g α e.g. 2-GABA . K cortex may additionally contribut + conductances, which knownto conductances, are α A 2-GABA receptor signal. Such an effect may be particularlyreceptor Such be may an effect signal. evid A R signal on the soma of MSNs (which make up an α 2-GABA an et al., 2014, Damodaran et al., 2015). 2015). al., et Damodaran 2014, al., et an ions and addictive behaviour remains largely ere GABA would ere normallyfacilitate incoming (see (see section 3.2.3). alsoInhibition be may entified a number of potential behavioural behavioural of potential number a entified and Chrobak, 1995, Gray, 1994). It is also It 1994). Gray, 1995, and Chrobak, tempting to speculate that if the effect of the effect speculate that if tempting to ationandglutamatergic of dopaminergic ined with a reductionined with a inhibition,in lateral A receptor-mediated conductance in ng, as previously demonstrated for both both for demonstrated previously as ng, emains a task to be undertaken. A R function, as suggested by R function, recent as suggested GABA A receptors in drug addictionreceptors and of the e to the the increased to e power of the larly weaken lateral inhibition inhibition lateral weaken larly modalities wherebymodalities different A the the receptor, integrating those be sensitive to changes in be sensitiveto changes al alterationsal in theMSN sociation provide studies β β with various addictions,with oscillation (Damodaran oscillation frequency frequency range under 3) and/or fast-spiking fast-spiking and/or 3) ent ent Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This variants have consequencesvariants for regulation of The advances in the understanding particular rolesof GABA to the neuronal addressed, system and the be pharmaceuticalmanipulation been systems has of GABAergic influencing actionsselective of drugs Hitherto, the ubiquitous role of GABAergic inhi intake. while animal data that suggest deletion of GABRA1 alcohol, but also suggest play they a role in conseque important has manipulation their that For the moment, we can point Forwe moment, to the Nevertheless, available the presently data are consistent with of respective interrogation physiological their different receptor isoforms wi tools for understanding are as needed, urgently appear appear toin be associated reward-conditionedbehaviour, while variants in the genes unknown) role in striatal inhibition, and to interactions b to addictive behaviour. answ clear A α GABRA4 It is a curiosity that while no humangene in protecting againstfactorspredisposing to addictive be worthwhileto investigate whether selective facilitation of weWhile are still some fromway a providing subtype receptor specific targeting worthwhile be might aspects of addictive behaviour outlined in review, this 4-GABA polymorphisms and addictions, withinan A polymorphisms associating not have identifiedbeen with as receptors have suggested they play an im a complexwithbehavioural fashion traits predisposing ( thin neuronal specific populations and cellular domains, an α2 er toer the question of whether human -GABA aspects of psychostimulant Similarly,reward. this subunit decreases alcohol (and sucrose) GABAergic transmission has that meant GABAergic tic associationtic data providebetween a link A rational therapeutic approach, it would seem α2− roles within the relevant neuronal networks. networks. neuronal relevant the within roles receptors as playing an important (albeit (albeit important an playing as receptors bition across thebition entirebrain, across and the non- havioural consequences of drug treatment. the the spatial and temporal organisation of the nces fornces motivation to obtain and consume GABA imal studies, discreteimal manipulations of portantrole in striatalphysiology, and haviour. now tohold begin promise that it etween psychostimulant drugs and A A s to influence addictive behaviour. behaviour. addictive to s influence receptor expressionreceptor in people is encoding those receptors same

A α non-specific,bothwith regard receptor receptor subtype in different 2-GABA a role of A receptors mightreceptors be α2 human addictions, -GABA GABRA2 A receptors inter alia gene d ) Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This This reviewThis is a considerably extended version of the l Acknowledgements been have prototypes useful for controlling addictive behaviours. While Walker. The authors declare they have no conflicts of in Macpherson, ScottEd Maguire, Mitchell, Hannah Jer Morris, tohavesay In here. particular,Dixon, thank Claire we Be review,outlined this though, needless to within tostudents both data collection, and more acknowledge the important contributions of European Commission by the and G1000008), G0802715, Addic Council Medical by the UK Research from Research 2015. Sweden in May, Uppsala, from IB Distinguished Award Scientist the himreceiving developed (Atack, 2011). 2011). (Atack, developed importantly to the development of ideas the authors’ own laboratories was supported the authors’ own laboratories say, they may not agree with everything we everything with we they not may agree say, our colleagues, postdocs and graduate tion Cluster “GABA” (Grants G0600874, G0600874, “GABA” (Grants tion Cluster not drugs are such yet available clinically, ecture given byecture of DNS at the time eet terest. ANGS at its annual its in meeting ANGSat n Gunn, Herd, Murray Tom FP6 project IMAGEN. We IMAGEN. We FP6 project ome Swinny and Sophie Sophie omeSwinny and Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This BELELLI , D. & LAMBERT, J. J. 2005. Neurostero 2005. J. J. LAMBERT, & D. , BELELLI BELELLI , D., HARRI SON, N. L., MAGUI RE, J., MACDONAL J., RE, MAGUI L., N. SON, HARRI D., , BELELLI BECKER, H. C. & HALE, R. L. 1993. Repeated ep Repeated 1993. L. R. HALE, & C. H. BECKER, BAUER, L. O. & HESSELBROCK, V. M. 1993. EEG, autono EEG, 1993. M. V. HESSELBROCK, & O. L. BAUER, BATESON, A. N., LASHAM, A. & DARLI SON, M. G. 1991. 1991. G. M. SON, DARLI & A. LASHAM, N., A. BATESON, AMSEK,G,HFT . ETE,A,K RSCHSTEI KI A., AERTSEN, S., HEFFT, G., BARMASHENKO, ATACK, J. R. 2011. GABAA receptor subtype-sele receptor GABAA 2011. R. J. ATACK, ARI AS, A. J., COVAULT, J., FEI NN, R., POND, T., YAN T., POND, R., NN, FEI J., COVAULT, J., A. AS, ARI ARBUTHNOTT, G. W. & WI CKENS, J. 2007. Space, tim e a e tim Space, 2007. J. CKENS, WI & W. G. ARBUTHNOTT, ANSTEE, Q. M., KNAPP, S., MAGUI RE, E. P., HOSI E, A. E, HOSI P., E. RE, MAGUI S., KNAPP, M., Q. ANSTEE, BI ERUT, L. J., AGRAWAL, A., BUCHOLZ, K. K., DOHENY, K., K. BUCHOLZ, A., AGRAWAL, J., L. ERUT, BI AGRAWAL, A., MORLEY, K. I ., HANSELL, N. K., PERGADI K., N. HANSELL, ., I K. MORLEY, A., AGRAWAL, GAA,A,PRAIA .L,SCOE .F,H NRI HI F., S. SACCONE, L., M. A, PERGADI A., AGRAWAL, BENI NGER, R. J. & PHI LLI PS, A. G. 1980. The e The 1980. G. A. PS, LLI PHI & J. R. NGER, BENI BELL, M. V., BLOOMFI ELD, J., MCKI NLEY, M., PATTERSO M., NLEY, MCKI J., ELD, BLOOMFI V., M. BELL, BERGESON, S. E., KYLE WARREN, R., CRABBE, J. C., ME C., J. CRABBE, R., WARREN, KYLE E., S. BERGESON, AGRAWAL, A., EDENBERG, H. J., FOROUD, T., BI ERUT, L ERUT, BI T., FOROUD, J., H. EDENBERG, A., AGRAWAL, D,K . ASE,M . RINK .I.&V IN CI VI & . I P. , NSKI ORTI J., M. JANSSEN, K., K. ADE, References BELELLI , D., PEDEN, D. R., ROSAHL, T. W., WAFFORD, WAFFORD, W., T. ROSAHL, R., D. PEDEN, D., , BELELLI 12757-63. 12757-63. receptor. receptor. 09 xrsnpi AA eetr: om,pamaco pharm , form receptors: GABAA Extrasynaptic 2009. severity of subsequent withdrawal seizures withdrawal "kindling". subsequent of severity for alcoholism . . alcoholism for heterogeneity is increased by alternative splici alternative by increased is heterogeneity erce , Neurochem widespread after status epilepticus. due epilepticus. status potential after reversal widespread receptor GABAA the of shifts agonists as non-sedating anxiolytics. anxiolytics. non-sedating as agonists alcohol adm inistration. wi inistration. associated is adm alcohol variant GABRA2 A 2014. R. H. ar1gn rmoeachlcnu ptio consum un, m alcohol Com ote prom THOMAS, gene & G. T. Gabrb1 SMART, Y., J., J. M. LAMBERT, MORGAN, D., M., , H. BELELLI NG, GUER GURLI ., A., I M. NSON, UNGLESS, ROBI M., RUPAD., J. ., BELL, I C. A., HY, XON, HERLI DI T., E., Y. S. WALKER, A., NEZ, MARTI R., HATSUKAMI , D., HESSELBROCK, V., JOHNSON, E. O., KRA O., E. JOHNSON, V., HESSELBROCK, F J., D., , H. EDENBERG, HATSUKAMI M., D. L CK, A. DI CHS, C., NRI R. HI CULVERHOUSE, S., BERTELSEN, W., HOWELLS, L., FOX, dependence: evidence for association from a case-co a from r acid association yric for inobut evidence a-am m Gam dependence: 2008b. GOA A. P. G., N. MADDEN, N, & J. MARTI C., A. HEATH, JOHNSON W., G. N., MONTGOMERY, BRESLAU, J., R. NEUMAN, L., N. SACCONE, LYNSKEY, M. T. 2008a. Autosom al linkage analys linkage al adults. WH C., Autosom A. HEATH, 2008a. A., T. P. M. LYNSKEY, MADDEN, D., R. TODD, J., D. eo e, Genom DXS374 locus in hum an Xq28. Xq28. GABA an a of hum in linkage locus Physical DXS374 1989. E. K. ES, DAVI & A. K. 2003. Chrom osom al loci influencing influencing loci al osom Chrom 2003. K. 25 collaborative study of the genetics of alcoholism s alcoholism of genetics the of study Associatio collaborative 2006. M. D. CK, DI & SCHUCKI B. PORJESZ, S., KUPERMAN, R., CROWE, ., I J. NURNBERGER, conductances in striatal m edium spiny neurons. neurons. spiny edium m striatal in conductances conditioned reinforcem ent. ent. reinforcem conditioned AA eetr ftaa cria ern: olec m a neurons: ocortical thalam of receptors GABAA , 11513-20. 11513-20. Drug Alcohol Depend Alcohol Drug 14 4 Nat Rev Neurosci, Rev Nat Alcohol Clin Exp Res, Exp Clin Alcohol , 56 , 2816. 2816. 454-63. 454-63. , J Stud Alcohol, Stud J 1437-40. 1437-40. Alcohol Alcohol, Alcohol Psychopharm acology (Berl), acology Psychopharm 6 . . , 54 565-75. 565-75. Am J Hum Genet, Hum J Am 17 , 577-89. 577-89. , 94-8. 94-8. Epilepsia, urTpMdCe , Chem Med Top Curr 49 , 1-9. 1-9. chronic alcohol withdrawal severity. severity. withdrawal alcohol chronic ids: endogenous regulators of the GABA(A) GABA(A) the of regulators endogenous ids: ctive m odulators. I . alpha2/ alpha3-selective alpha3-selective alpha2/ . I odulators. m ctive isodes of ethanol withdrawal potentiate the the potentiate withdrawal ethanol of isodes 52 n through increased tonic inhibition. inhibition. tonic increased through n ffect of pim ozide on the establishm ent of of ent establishm the on ozide pim of ffect : an anim al m odel of alcohol withdrawal withdrawal alcohol of odel m al anim an : G, B. Z., GE, W., ONCKEN, C. & KRANZLER, KRANZLER, & C. ONCKEN, W., GE, Z., B. G, ng of a novel beta-subunit gene transcript. transcript. gene beta-subunit novel a of ng n of GABRA2 with drug dependence in the the in dependence drug with GABRA2 of n th increased stim ulation and 'high' following following 'high' and ulation stim increased th M., THOMAS, P., MORTENSEN, M., BHOME, BHOME, M., MORTENSEN, P., THOMAS, M., K. A. & LAMBERT, J. J. 2005. Extrasynaptic Extrasynaptic 2005. J. J. LAMBERT, & A. K. J Neurosci, J 45 A, M. L., MONTGOMERY, G. W., STATHAM, STATHAM, W., G. MONTGOMERY, L., M. A, , N, M. N., DARLI SON, M. G., BARNARD, E. E. BARNARD, G., M. SON, DARLI N., M. N, K. F., LAURI E, C., PUGH, E., FI SHER, S., S., SHER, FI E., PUGH, C., E, LAURI F., K. is for cannabis use behaviors in Australian Australian in behaviors use cannabis for is nd dopam ine. ine. dopam nd TTEN, P., GENE ERWI N, V. & BELKNAP, J. J. BELKNAP, & V. N, ERWI GENE P., TTEN, 1570-8. 1570-8. am ple. ple. am CHS, A. L., LESSOV-SCHLAGGAR, C. N., N., C. LESSOV-SCHLAGGAR, L., A. CHS, D, R. L., WALKER, M. C. & COPE, D. W. W. D. COPE, & C. M. WALKER, L., R. D, m ic and subjective correlates of the risk risk the of correlates subjective and ic m , 883-8. 883-8. ntrol study. study. ntrol I , S. 2008. Differential tonic GABA GABA tonic Differential 2008. S. , I N, T. & KOHLI NG, R. 2011. Positive Positive 2011. R. NG, KOHLI & T. N, gam m a-Am inobutyric acidA receptor receptor acidA inobutyric a-Am m gam . J., DUNNE, G., HI NRI CHS, A. L., L., A. CHS, NRI HI G., DUNNE, J., . ular target for hypnotics. hypnotics. for target ular RI NI , I ., MCQUI LLI N, A., FI SHER, E. E. SHER, FI A., N, LLI MCQUI ., I , NI RI to altered chloride hom eostasis is is eostasis hom chloride altered to 68 RELI A, K., MONTAGNESE, S., KUO, KUO, S., MONTAGNESE, K., A, RELI logy, and function. function. and logy, BROWN, S. D., STEPHENS, D. N., N., D. STEPHENS, D., S. BROWN, Behav Genet, Behav A receptor subunit gene to the the to gene subunit receptor A TE, A. M., RI CE, J. P., BI ERUT, L. L. ERUT, BI P., J. CE, RI M., A. TE, 11 , 28 H. C. 2013. Mutations in the the in Mutations 2013. C. H. 147-53. 147-53. I TFI ELD, J., MARTI N, N. G. & & G. N. N, MARTI J., ELD, TFI I ., ALMASY, L., BRESLAU, N., N., BRESLAU, L., ALMASY, ., OROUD, T., GRUCZA, R. A., A., R. GRUCZA, T., OROUD, , 1176-202. 1176-202. eceptor genes and nicotine nicotine and genes eceptor , 1185-97. 1185-97. MER, J., KRUEGER, R. F., F., R. KRUEGER, J., MER, Trends Neurosci, Trends T, M. A., BEGLEI TER, H., H., TER, BEGLEI A., M. T, Addiction, , E., HATSUKAMI , D., D., , HATSUKAMI E., , 36 , 640-50. 640-50. 103 J Neurosci, J , 1027-38. 1027-38. 30 J Neurosci, J , 62-9. 62-9. a m Mam 29 Nat Nat J ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This CADET, J. L. 2016. Epigenetics of Stress, Addiction Stress, of Epigenetics 2016. L. J. CADET, C A G E T T I ,E . ,L I A N G ,J . ,S P I G E L M A N ,I .& O L S E N ,R .W USK .&CRBK .J 95 e poral Tem 1995. J. J. CHROBAK, & G. , BUZSAKI BUCK, K. J., METTEN, P., BELKNAP, J. K. & CRABBE, CRABBE, & K. J. BELKNAP, P., METTEN, J., K. BUCK, BUTKOVI CH, L. M., DEPOY, L. M., ALLEN, A. G., SHAPI G., A. ALLEN, M., L. DEPOY, M., L. CH, BUTKOVI BROWMAN, K. E. & CRABBE, J. C. 2000. Quantitative t Quantitative 2000. C. J. CRABBE, & E. K. BROWMAN, BRI CKLEY, S. G., REVI LLA, V., CULL- CANDY, S. G., WI G., S. CANDY, CULL- V., LLA, REVI G., S. CKLEY, BRI BUCKLE, V. J., FUJI TA, N., RYDER-COOK, A. S., DERRY S., A. RYDER-COOK, N., TA, FUJI J., V. BUCKLE, RW,M . A,K . 'ONR .C,N KONENK NI C., E. O'CONNOR, R., K. TAN, T., M. BROWN, ETNI,S . EPN . ISE,M . LM NG FLEMI L., M. SHER, RI T., TEPPEN, W., S. , CENTANNI BRACCI , E. & PANZERI , S. 2006. Excitatory GABAergic Excitatory 2006. S. , PANZERI & E. , BRACCI BOEHM, S. L., 2ND, PONOMAREV, I ., JENNI NGS, A. W., W., A. NGS, JENNI ., I PONOMAREV, 2ND, L., S. BOEHM, CAPRI OLI , D., SAWI AK, S. J., MERLO, E., THEOBALD, D THEOBALD, E., MERLO, J., S. AK, SAWI D., , OLI CAPRI CAGNI ARD, B., BEELER, J. A., BRI TT, J. P., MCGEHEE, P., J. TT, BRI A., J. BEELER, B., ARD, CAGNI CAGNI ARD, B., BALSAM, P. D., BRUNNER, D. & ZHUA & D. BRUNNER, D., P. BALSAM, B., ARD, CAGNI CAMMAROTA, M., I ZQUI ERDO, I ., WOLFMAN, C., LEVI DE DE LEVI C., WOLFMAN, ., I ERDO, ZQUI I M., CAMMAROTA, BLEDNOV, Y. A., BORGHESE, C. M., MCCRACKEN, M. L., L., M. MCCRACKEN, M., C. BORGHESE, A., Y. BLEDNOV, BLEDNOV, Y. A., JUNG, S., ALVA, H., WALLACE, D., RO D., WALLACE, H., ALVA, S., JUNG, A., Y. BLEDNOV, BLEDNOV, Y. A., WALKER, D., ALVA, H., CREECH, K., F K., CREECH, H., ALVA, D., WALKER, A., Y. BLEDNOV, Neurobiol, regulation of neuronal excitability by a voltage-in a by excitability Nature, neuronal of regulation Chrom osom al localization of GABAA receptor subunit subunit receptor GABAA of disease. localization D al N., osom A. Chrom BATESON, H., P. SEEBURG, R., P. ELD, SCHOFI ensem bles: a role for interneuronal networks. networks. interneuronal for role a bles: ensem enhance associative learning. pa learning. projections associative GABA area enhance ental tegm Ventral L. 2015. Adolescent-onset GABAA alpha1 silencing re silencing alpha1 GABAA aking. m Adolescent-onset 2015. L. recom binant inbred m ice. ice. m inbred binant recom genetic predisposition to acute alcohol withdrawal withdrawal alcohol acute to predisposition genetic Neurophysiol, subunit m utant m ice: new perspectives on alcohol ac alcohol on perspectives new ice: a-A m m gam utant m 2004. A. R. subunit S, HARRI & A. Y. BLEDNOV, M., E. 602. 602. underlie trait-like im pulsive behavior. ark behavior. m pulsive im structural neuronal trait-like and underlie acidergic inobutyric N am ROBBI J., B. TT, EVERI A., CARPENTER,T. MULHOLLAND, P. J., PANDEY, S. C., CHANDLER, L. J. & J. L. CHANDLER, C., S. PANDEY, J., P. MULHOLLAND, Dopam ine scales perform ance in the absence of new l new of absence the in ance perform scales ine Dopam 2003a. Deletion of t he alpha1 or beta2 subunit of G of subunit drugs. beta2 or other alpha1 and he t alcohol of Deletion 2003a. selective changes in 3[ H] AMPA receptor binding in t in binding , Mem Learn receptor AMPA H] 3[ Neurobiol in changes selective EUAINK,D EIN,J .19.Inhi I 1995. H. J. NA, MEDI & D. NSKY, JERUSALI receptors. receptors. m otor stim ulation in knockin m ice with et with ice m knockin in ulation Loss stim 2011. otor A. m R. S, HARRI & E. G. S CS, S., YER, HOMANI I F., D. WERNER, E., OSTERNDORFF-KAHANEK, eetrapa1adbt uui ulmuta m null Ther, subunit Exp 2 acol beta Pharm and 1 alpha receptor dopam ine exhibit enhanced m otivation, acology, otivation, m Neuropsychopharm enhanced exhibit ine dopam nemitn tao rametcagssbntcmp com positive to acol, subunit Pharm responses Mol changes ent behavioral treatm decreases and ethanol ittent interm S. C. 2010. A genom e- wide association study of alco of study association wide e- genom A GOAT M., ETSCHEL, 2010. RI C. C., S. J. WANG, L., N. A., J. SACCONE, ELD, M., SCHFI NGER, TI DI RI B., PORJESZ, J., JR., R. ., NEUMAN, I K., MANN, M., LYNSKEY, S., KUPERMAN, S A, S 107 409 , Eur J Neurosci, J Eur Neuron, 5082-7. 5082-7. 53 J Pharm acol Exp Ther, Exp acol Pharm J , 88-92. 88-92. , 95 545-60. 545-60. 63 3 , 1285-90. 1285-90. , , 53-64. 53-64. 647-54. 647-54. 305 64 42 J Pharm acol Exp Ther, Exp acol Pharm J , , 854-63. 854-63. 257-64. 257-64. Alcohol Clin Exp Res, Exp Clin Alcohol , 2114-21. 2114-21. 31 Nature, , 1362-70. 1362-70. 336 , 492 Biol Psychiatry, Biol 145-54. 145-54. , 452-6. 452-6. , and Resilience: Therapeutic I m plications. plications. m I Therapeutic Resilience: and , hanol-insensitive alpha2-containing GABA(A) GABA(A) alpha2-containing hanol-insensitive structure in spatially organized neuronal neuronal organized spatially in structure NG, X. 2006a. Mice with chronically elevat ed ed elevat chronically with Mice 2006a. X. NG, J. C. 1997. Quantitative trait loci involved in in involved loci trait Quantitative 1997. C. J. Curr Opin Neurobiol, Opin Curr D. S., MARI NELLI , M. & ZHUANG, X. 2006b. 2006b. X. ZHUANG, & M. , NELLI MARI S., D. but not learning, for a food reward. reward. food a for learning, not but S, T. W. & DALLEY, J. W. 2014. Gam m a a m Gam 2014. W. J. DALLEY, & W. T. S, 24 304 nt m ice: behavioral responses to ethanol. ethanol. to responses behavioral ice: m nt RO, L. P., SWANSON, A. M. & GOURLEY, S. S. GOURLEY, & M. A. SWANSON, P., L. RO, bitory avoidance training induces rapid and and rapid induces training avoidance bitory I NDLAY, G. & HARRI S, R. A. 2003b. GABAA GABAA 2003b. A. R. S, HARRI & G. NDLAY, I use accum bal cholinergic interneurons to to interneurons cholinergic bal accum use rait loci affecting ethanol sensitivity in BXD BXD in sensitivity ethanol affecting loci rait allosteric m odulators of GABAA receptors. receptors. GABAA of odulators m allosteric SAHL, T., WHI TI NG, P. J. & HARRI S, R. A. A. R. S, HARRI & J. P. NG, TI WHI T., SAHL, WHI TI NG, P. J., ROSAHL, T. W., GARRETT, GARRETT, W., T. ROSAHL, J., P. NG, TI WHI SDEN, W. & FARRANT, M. 2001. Adaptive Adaptive 2001. M. FARRANT, & W. SDEN, of ethanol conditioned taste aversion and and aversion taste conditioned ethanol of . E., SPOELDER, M., JUPP, B., VOON, V., V., VOON, JUPP,B., M., SPOELDER, E., . effects in striatal projection neurons. neurons. projection striatal in effects , O, I ., MULLER, D. & LUSCHER, C. 2012. 2012. C. LUSCHER, & D. MULLER, ., I O, in m ice. ice. m in , J. M., BARNARD, P. J., LEBO, R. V., V., R. LEBO, J., P. BARNARD, M., J. , , R. L., MOSS, J. L., ACHESON, S. K., K., S. ACHESON, L., J. MOSS, L., R. , 17-23. 17-23. , 30-6. 30-6. 75 hol dependence. dependence. hol earning. earning. genes: relationship to hum an genetic genetic an hum to relationship genes: tions. tions. dependent potassium conductance. conductance. potassium dependent ers in the nucleus accum bens core core bens accum nucleus the in ers SACCONE, S. F., SCHUCKI T, M. A., A., M. T, SCHUCKI F., S. SACCONE, .2 0 0 3 .W i t h d r a w a lf r o mc h r o n i c ABAA recept ors reduces act ions of of ions act reduces ors recept ABAA osition, reduces synaptic function, function, synaptic reduces osition, E, A. M., RI CE, J. P. & GENE, E. A. A. E. GENE, & P. J. CE, RI M., A. E, BENAVI DEZ, J. M., GEI L, C. R., R., C. L, GEI M., J. DEZ, BENAVI , NOTHEN, M. M., NURNBERGER, J. J. NURNBERGER, M., M. NOTHEN, 115-23. 115-23. ARLI SON, M. G. & ET AL. 1989. 1989. AL. ET & G. M. SON, ARLI he rat hippocam pal form at ion. ion. at form pal hippocam rat he gulates reward-related decision decision reward-related gulates J Neurosci, J SWARTZWELDER, H. S. 2014. 2014. S. H. SWARTZWELDER, WI HART, A., HARRI SON, N. L., L., N. SON, HARRI A., HART, WI ice Pamacol, Pharm Biochem STEI N, M., BERNABEU, R., R., BERNABEU, M., N, STEI m inobutyric acid A receptor receptor A acid inobutyric m Neuron, 5 , 504-10. 504-10. 17 51 Proc Natl Acad Sci U U Sci Acad Natl Proc , 3946-55. 3946-55. , 541-7. 541-7. 68 , 1581- Mol Mol J J Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This CROW, T. J. 1972. A map of the rat mesencephalon fo mesencephalon rat the of map A 1972. J. T. CROW, RBE .C,PILIP,T . UK .J,CNIN CUNNI J., K. BUCK, J., T. PS, LLI PHI C., J. CRABBE, CRABBE, J. C., BELKNAP, J. K., MI TCHELL, S. R. R. S. TCHELL, MI K., J. BELKNAP, C., J. CRABBE, ORD .L,TEG .Y,UJ A .L,RIMERS REI L., J. MA, UEJI Y., K. TSENG, L., K. CONRAD, COSTA, L. & BAUER, L. 1997. Quantitative elec Quantitative 1997. L. BAUER, & L. COSTA, COVAULT, J., GELERNTER, J., HESSELBROCK, V., NE V., HESSELBROCK, J., GELERNTER, J., COVAULT, COVAULT, J., GELERNTER, J., JENSEN, K., ANTON, R. & R. ANTON, K., JENSEN, J., GELERNTER, J., COVAULT, COSTA, R. M., LI N, S. C., SOTNI KOVA, T. D., CYR, M. CYR, D., T. KOVA, SOTNI C., S. N, LI M., R. COSTA, COLLI NSON, N., ATACK, J. R., LAUGHTON, P., DAWSON, DAWSON, P., LAUGHTON, R., J. ATACK, N., NSON, COLLI CLONI NGER, C. R., SI GVARDSSON, S., GI LLI GAN, S. B., S. GAN, LLI GI S., GVARDSSON, SI R., C. NGER, CLONI CHEN, Q., LEE, T. H., WETSEL, W. C., SUN, Q. A., LI A., Q. SUN, C., W. WETSEL, H., T. LEE, Q., CHEN, CHESLER, E. J., WANG, J., LU, L., QU, Y., MANLY, K. MANLY, Y., QU, L., LU, J., WANG, J., E. CHESLER, D A M O D A R A N ,S . ,E V A N S ,R .C .& B L A C K W E L L ,K .T .2 0 1 4 DAMODARAN, S., CRESSMAN, J. CRESSMAN, S., DAMODARAN, DEAN, M., LUCAS-DERSE, S., BOLOS, A., O'BRI EN, S. J S. EN, O'BRI A., BOLOS, S., LUCAS-DERSE, M., DEAN, CZUBAYKO, U. & PLENZ, D. 2002. Fast synaptic transm synaptic Fast 2002. D. PLENZ, & U. CZUBAYKO, DI AS, R., SHEPPARD, W. F., FRADLEY, R. L., GARRETT, L., R. FRADLEY, F., W. SHEPPARD, R., AS, DI CHEN, C. H., HUANG, C. C. & LI AO, D. L. 2014. Assoc 2014. L. D. AO, LI & C. C. HUANG, H., C. CHEN, DI CHI ARA, G. & I MPERATO, A. 1988. Drugs abus Drugs 1988. A. MPERATO, I & G. ARA, CHI DI DI CK, D. M., AGRAWAL, A., SCHUCKI T, M. A., BI ERUT, ERUT, BI A., M. T, SCHUCKI A., AGRAWAL, M., D. CK, DI I dentifying genes for alcohol and drug sensitiv drug and Neurosci, alcohol for Trends genes dentifying I receptors m ediates incubation of cocaine craving. craving. cocaine of accu incubation of ediates ation m Form receptors 2008. E. M. WOLF, & M. , NELLI MARI m arkers in the adjacent GABRA2 gene. gene. GABRA2 adjacent the depend in alcohol arkers to m associate GABRG1 of region hypotherm ia in BXD recom binant inbred m ice. ice. m inbred and binant recom sensitivity BXD in the ia influence hypotherm that genes of apping m (Berl), alcohol, cocaine, heroin and dual-substance depende dual-substance and heroin cocaine, alcohol, NI COLELI S, M. A. 2006. Rapid alterations in in ine-depende dopam alterations Rapid acute 2006. A. M. S, COLELI NI Neuropsychiatr Genet, GA of Neuropsychiatr association haplotypic and encoding and recall but not consol not but subunit-contai recall alpha5 and for encoding selective agonist inverse BOHMAN, M. 1988. Genetic heterogeneity and the clas the and Abuse, heterogeneity Subst Genetic 1988. M. BOHMAN, zeta activity. re GABAA and activity. GAD67 coca zeta alizes of norm Reversal 2007. sensitization X. ZHANG, & H. E. NWOOD, ELLI explore neurobehavioral phenotypes. inbred phenotypes. binant recom in neurobehavioral explore expression gene of correlates mblnei iigi h oa n-elte triat st ed ine-deplet dopam the in interneu firing in balance fast-spiking im of Desynchronization with heroin dependence. dependence. heroin with interneurons is critical to m aintain balanced firin . balanced striatum aintain the m of to neurons critical is interneurons ho sme4 sn erncetd eetplmo polym repeat tetranucleotide a th using of 4, e osom apping m chrom Genetic 1991. D. GOLDMAN, 265-73. 265-73. neurons. neurons. Sci U S A, S U Sci the anxiolytic effects of benzodiazepines. benzodiazepines. of alph of effects role anxiolytic significant the a for DAWSO Evidence M., R. MCKERNAN, 2005. R., J. ATACK, J., L. W., STREET, T. A., ROSAHL, K. WAFFORD, A., CONLEY, S. M., THOMPSON, S. C., COOK, J., R. NCOLN, LI S., GOODACRE, dopam ine concentrations in the m esolim bic system of system bic esolim m the in concentrations ine dopam Adolescent alcohol exposure alters GABAA receptor s receptor GABAA pus. alters hippocam exposure alcohol Adolescent PORJESZ, B., EDENBERG, H. & BEGLEI TER, H. H. TER, BEGLEI & H. EDENBERG, I B., J. PORJESZ, NURNBERGER, V., HESSELBROCK, R., C. NGER, CLONI 188 Proc Natl Acad Sci U S A, S U Sci Acad Natl Proc 85 , 619-28. 619-28. , 7 ice BohsRsCmmun, m Com Res Biophys Biochem 5274-8. 5274-8. Alcohol Clin Exp Res, Exp Clin Alcohol , 3-16. 3-16. 22 , 173-9. 173-9. 129B J Neurophysiol, J PLoS One, PLoS nt m otor dysfunction. dysfunction. otor m nt R., JEDRZEJEWSKI -SZMEK, Z. -SZMEK, JEDRZEJEWSKI R., , 104-9. 104-9. 99 BRA2 with alcohol dependence. dependence. alcohol with BRA2 idation in the Morris water m aze. aze. m water Morris the in idation 38 9 , , erifr atics, Neuroinform e102227. e102227. 15764-9. 15764-9. , 2800-8. 2800-8. erpyhpamacology, Neuropsychopharm 111 J Neurosci, J & CRAWSHAW, L. I . 1994. Quantitative trait loci loci trait Quantitative 1994. . I L. CRAWSHAW, & troencephalographic differences associated with with associated differences troencephalographic ed by hum ans preferentially increase synaptic synaptic increase preferentially ans hum by ed , LLI SSERY, M. & KRANZLER, H. R. 2004. Allelic Allelic 2004. R. H. KRANZLER, & M. SSERY, LLI a 3-containing GABAA receptors in m ediating ediating m in receptors GABAA 3-containing a 356 836-48. 836-48. rons reduces beta-band oscillations and and oscillations beta-band reduces rons otcsraa ne ble ensem corticostriatal iation analysis of GABRB3 prom oter variants variants oter prom GABRB3 of analysis iation J Pharm acol Exp Ther, Exp acol Pharm J e beta 1 GABA receptor gene to hum an an hum to gene receptor GABA 1 beta e ceptor alpha2 subunit expression, and PKC and expression, subunit alpha2 ceptor ence and are in linkage disequilibrium with with disequilibrium linkage in are and ence Neuron, 2006a. Marital status, alcohol dependence, dependence, alcohol status, Marital 2006a. ity: recent progress and future directions. directions. future and progress recent ity: KRANZLER, H. R. 2008. Markers in the 5'- the in Markers 2008. R. H. KRANZLER, r electrical self-stim ulation. ulation. self-stim electrical r L., HI NRI CHS, A., FOX, L., MULLANEY, J., J., MULLANEY, L., FOX, A., CHS, NRI HI L., , GAI NETDI NOV, R. R., CARON, M. G. & & G. M. CARON, R., R. NOV, NETDI GAI , , Nature, F. & WI LLI AMS, R. W. 2003. Genetic Genetic 2003. W. R. AMS, LLI WI & F. 733-8. 733-8. GHAM, C. L. & BELKNAP, J. K. 1999. 1999. K. J. BELKNAP, & L. C. GHAM, um . . um ission between striatal spiny projection projection spiny striatal between ission g between direct and indirect pathway pathway indirect and direct between g ., KI RKNESS, E. F., FRASER, C. M. & & M. C. FRASER, F., E. RKNESS, KI ., VON KNORRI NG, A. L., REI CH, T. & & T. CH, REI L., A. NG, KNORRI VON 25 E. M., STANLEY, J. L., TYE, S. J., J., S. TYE, L., J. STANLEY, M., E. nce. nce. strains: a relat ional m odel syst em to to em syst odel m ional relat a strains: , J. M., HENG, L. J., SHAHAM, Y., Y., SHAHAM, J., L. HENG, M., J. , G. R. & STEPHENS, D. N. 2006. An An 2006. N. D. STEPHENS, & R. G. U, Y., DAVI DSON, C., XI ONG, X., X., ONG, XI C., DSON, DAVI Y., U, rphism . . rphism .S y n c h r o n i z e df i r i n go ff a s t - s p i k i n g freely m oving rats. rats. oving m freely J Neurosci, J sification of alcoholism . . alcoholism of sification 52 1 ine sensitization-induced behavioral behavioral sensitization-induced ine , ning GABAA receptors im proves proves im receptors GABAA ning 10682-8. 10682-8. , CASTRO, J. L., WHI TI NG, P. J., J., P. NG, TI WHI L., J. CASTRO, 454 R., HALLETT, D., HUMPHRI ES, A. A. ES, HUMPHRI D., HALLETT, R., Drug Alcohol Depend, Alcohol Drug 343-57. 343-57. , tolerance to ethanol-induced ethanol-induced to tolerance ., JR., ALMASY, L., FOROUD, T., T., FOROUD, L., ALMASY, JR., ., 359-69. 359-69. & BLACKWELL, K. T. 2015. 2015. T. K. BLACKWELL, & N, G. R. & REYNOLDS, D. S. S. D. REYNOLDS, & R. G. N, ubunit expression in adult adult in expression ubunit , m bens GluR2-lacking AMPA GluR2-lacking bens m Am J Hum Genet, Hum J Am 118-21. 118-21. 35 33 269 , 1149-59. 1149-59. Am J Med Genet B B Genet Med J Am Psychopharm acology acology Psychopharm , coordination during during coordination 837-48. 837-48. , 184-92. 184-92. Proc Natl Acad Acad Natl Proc Brain Res, Brain 46 Adv Alcohol Alcohol Adv 49 , , 87-93. 87-93. 621-6. 621-6. 36 ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This DI XON, C. I ., WALKER, S. E., KI NG, S. L. & STEP & L. S. NG, KI E., S. WALKER, ., I C. XON, DI DIXON, C. I., ROSAHL, T. W. & STEPHENS, D. N. 2008. DI XON, C. I ., HALB ., I C. XON, DI IXN .I. OR ,H . RE,G,DSIV ERES VI DESRI G., BREEN, V., H. S, MORRI ., I C. XON, DI DI CK, D. M., SMI TH, G., OLAUSSON, P., MI TCHELL, S. S. TCHELL, MI P., OLAUSSON, G., TH, SMI M., D. CK, DI DI CK, D. M., PLUNKETT, J., WETHERI LL, L. F., XUEI , , XUEI F., L. LL, WETHERI J., PLUNKETT, M., D. CK, DI DI CK, D. M., LI , T. K., EDENBERG, H. J., HESSELBROC J., H. EDENBERG, K., T. , LI M., D. CK, DI DI CK, D. M., LATENDRESSE, S. J., LANSFORD, J. LANSFORD, J., S. LATENDRESSE, M., D. CK, DI DI CK, D. M. & FOROUD, T. 2003. Candidate genes for for genes Candidate 2003. T. FOROUD, & M. D. CK, DI DI CK, D. M., EDENBERG, H. J., XUEI , X., GOATE, A., A., GOATE, X., , XUEI J., H. EDENBERG, M., D. CK, DI DI CK, D. M., BI ERUT, L., HI NRI CHS, A., FOX, L., BUC L., FOX, A., CHS, NRI HI L., ERUT, BI M., D. CK, DI DUKA, T., NI KOLAOU, K., KI NG, S. L., BANASCHEWSKI , , BANASCHEWSKI L., S. NG, KI K., KOLAOU, NI T., DUKA, DI CK, D. M., ALI EV, F., LATENDRESSE, S., PORJESZ, B PORJESZ, S., LATENDRESSE, F., EV, ALI M., D. CK, DI UC . NC,M . UT . IRKKU VI S., FUNT, A., M. ENOCH, F., , DUCCI DUKA, T., DI XON, C. I ., TRI CK, L., CROMBAG, CROMBAG, L., CK, TRI ., I C. XON, DI T., DUKA, DRGON, T., D'ADDARI O, C. & UHL, G. R. 2006. 2006. R. G. UHL, & C. O, D'ADDARI T., DRGON, results in hypersensitivity to the acute effect acute the to inistration. adm hypersensitivity in results em otional response, and abolishes anxiolytic effect Behav, anxiolytic Biochem abolishes acol and Pharm response, of otional em alpha2-subunits encoding subunit does not alt er self adm inistration of cocai of (Berl), inistration adm acology self er Psychopharm alt not does subunit alpha2 subunit-containing GABAA receptors. receptors. GABAA iv incent ouse m on subunit-containing effects alpha2 Cocaine NG KI J., 2010. J. N. LAMBERT, D. D., , MESSAS BELELLI R., R., RA, D. LARANJEI PEDEN, C., R., , NI NDALI GUI H., VALLADA, SHER, K. 2010. Understanding the construct of impul of construct the disorders. use Understanding 2010. K. SHER, GABRA1 and drinking behaviors in the collaborative collaborative the in ple. sam behaviors drinking FOROUD, and & GABRA1 J. H. EDENBERG, R., CROWE, M., T, SCHUCKI wide screen for genes influencing conduct disorder. conduct influencing genes for screen J. NURNBERGER, wide A., GOATE, K., BUCHOLZ, B., PORJESZ, across developm ent and evidence of m oderation by pa by oderation m of evidence and ent GABR of Role developm across 2009. E. J. BATES, & S. G. T, PETTI scitry, Psychiat evidence from hum an studies. studies. an hum from evidence Genet B Neuropsychiatr Genet, Neuropsychiatr B Genet with alcoholism in the collaborative study on the g the on study collaborative the r in GABAA the of alcoholism with association No 2005. T. FOROUD, & R. developm ental stages. stages. an ental disorder developm conduct for J. risk H. in EDENBERG, GABRA2 X., , XUEI E JR., SCHFI J., TI NURNBERGER, L., H., ALMASY, M., T, SCHUCKI V., HESSELBROCK, sensitivity in hum an adolescents. eas m adolescents. an during hum in responses brain ered sensitivity alt h GABRB1 wit ed press. in associat N. D. ETSCH STEPHENS, RI & G. T., PAUS, SCHUMANN, M., J.-L., NOT, MARTI P., NAT, GALLI GOWLAND, H., T., FLOR, J., P. CONROD, M., F. CARVALHO, tg fettegnsw id GBA n mpulsiv im and GABRA2 find: we genes the affect stage KRAMER, & S. KUPERMAN, K., BUCHOLZ, J., AGRA J., NURNBERGER, H., EDENBERG, V., HESSELBROCK, Motivational Effects of Methylphenidate are Associa are Risk. ion Methylphenidate of Addict Effects Motivational 67 antisocial personality disorder across three divers three across disorder in ilarities sim personality other antisocial and anxiety ncreased I studies of a chrom osom e 4 GABA receptor gene cluste gene receptor GABA ions. 4 e addict osom chrom a of studies and GABRA2: evidence for gene-environ for evidence GABRA2: and , 185-94. 185-94. Alcohol Clin Exp Res, Exp Clin Alcohol 66 Am J Med Genet B Neuropsychiatr Genet, Neuropsychiatr B Genet Med J Am OUT, B., KI NG, S. L. & STEPHENS, D. N. 2014. Deleti 2014. N. D. STEPHENS, & L. S. NG, KI B., OUT, , Addict Biol, Addict 649-57. 649-57. Front Behav Neurosci, Behav Front PLoS One, PLoS Behav Genet, Behav 15 7 90 , 231 e47135. e47135. , 30 217-26. 217-26. GABA(A) receptors facilitates perform ance of a cond a of ance perform facilitates receptors GABA(A) , Alcohol Clin Exp Res, Exp Clin Alcohol 132B 1-8. 1-8. , , 2695-703. 2695-703. 1101-10. 1101-10. Frontiers in Behavioral Neuroscience Behavioral in Frontiers 36 , 9 24-8. 24-8. , , 304. 304. 577-90. 577-90. NEN, M., ALBAUGH, B. & GOLDMAN, D. 2007. 2007. D. GOLDMAN, & B. ALBAUGH, M., NEN, Linkage disequilibrium , haplotype and association association and haplotype , disequilibrium Linkage m ent correlation and interaction. interaction. and correlation ent m HENS, D. N. 2012. Deletion of the gabra2 gene gene gabra2 the of Deletion 2012. N. D. HENS, H. S., KI NG, S. L. & STEPHENS, D. N. 2015. 2015. N. D. STEPHENS, & L. S. NG, KI S., H. E., BUDDE, J. P., GOATE, A., DODGE, K. A., A., K. DODGE, A., GOATE, P., J. BUDDE, E., Proc Natl Acad Sci U S A, S U Sci Acad Natl Proc tem perament of alcoholics with and without without and with alcoholics of perament tem e-learning and hum an addiction are linked to to linked are addiction an hum and e-learning J. 2013. How phenotype and developm ental ental developm and phenotype How 2013. J. s of ethanol but does not alter ethanol self self ethanol alter not does but ethanol of s d alcohol and drug dependence across across dependence drug and alcohol d HESSELBROCK, V., SCHUCKI T, M., CROWE, CROWE, M., T, SCHUCKI V., HESSELBROCK, HOLZ, K. K., KRAMER, J., KUPERMAN, S., S., KUPERMAN, J., KRAMER, K., K. HOLZ, A2 in trajectories of externalizing behavior behavior externalizing of trajectories in A2 e populations. populations. e alcohol dependence: a review of genetic genetic of review a dependence: alcohol , S., JUGURNAUTH, S., STEI NER, R. C., C., R. NER, STEI S., JUGURNAUTH, S., , Targeted deletion of the GABRA2 gene ne or reinstatem ent of cocaine seeking. seeking. cocaine of ent reinstatem or ne H., LEEMAN, R. F., O'MALLEY, S. S. & & S. S. O'MALLEY, F., R. LEEMAN, H., enetics of alcoholism sam ple. ple. sam alcoholism of enetics

27 ., SCHUCKI T, M., RANGASWAMY, M., M., RANGASWAMY, M., T, SCHUCKI ., Mol Psychiatry, Mol s of benzodiazepines and barbiturates. barbiturates. and benzodiazepines of s 141B ted with GABRA2 Variants Conferring Conferring Variants GABRA2 with ted K, V., KRAMER, J., KUPERMAN, S., S., KUPERMAN, J., KRAMER, V., K, ity. ity. X., GOATE, A., HESSELBROCK, V., V., HESSELBROCK, A., GOATE, X., , S. L., SCHUMANN, G. & STEPHENS, STEPHENS, & G. SCHUMANN, L., S. , T., BOKDE, A. L. W., BÜCHEL, C., C., BÜCHEL, W., L. A. BOKDE, T., td ntegntc fachls alcoholism of genetics the on study sivity and its relationship to alcohol alcohol to relationship its and sivity , 868-79. 868-79. & FOROUD, T. 2006b. The role of of role The 2006b. T. FOROUD, & EL, M., ROBBI NS, T. W., SMOLKA, SMOLKA, W., T. NS, ROBBI M., EL, J., GARAVAN, H., HEI NZ, A., JI A, A, JI A., NZ, HEI H., GARAVAN, J., Twin Res Hum Genet, Hum Res Twin eceptor genes on chrom osom e 5 5 e osom chrom on genes eceptor ures of im pulsivit y and reward reward and y pulsivit im of ures &FRU,T 04 eo e- genom A 2004. T. FOROUD, & LD, J., PORJESZ, B., BEGLEI TER, TER, BEGLEI B., PORJESZ, J., LD, , G., ROSAHL, T. W., ATACK, J. J. ATACK, W., T. ROSAHL, G., , , snl uloieplmopim orphism polym nucleotide single r: candidate gene variants for for variants gene candidate r: 854-60. 854-60. T. 2006c. Association between between Association 2006c. T. rental m onitoring. onitoring. m rental WAL, A., BI ERUT, L., WANG, WANG, L., ERUT, BI A., WAL, Alcohol, on of the GABAA alpha2- GABAA the of on 9 , 81-6. 81-6. 107 . . 41 , 2289-94. 2289-94. , 3-12. 3-12. J Stud Alcohol, Stud J 16 Arch Gen Gen Arch Am J Med Med J Am , 661-9. 661-9. itioned itioned

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This FI NLAY, J. M., DAMSMA, G. & FI BI GER, H. C. 1992. Be 1992. C. H. GER, BI FI & G. DAMSMA, M., J. NLAY, FI FEHR, C., SANDER, T., TADI C, A., LENZEN, K. P., ANG P., K. LENZEN, A., C, TADI T., SANDER, C., FEHR, FARRANT, M. & NUSSER, Z. 2005. Variations on an inh an on Variations 2005. Z. NUSSER, & M. FARRANT, EVERI TT, B. J. & ROBBI NS, T. W. 2013. From the vent the From 2013. W. T. NS, ROBBI & J. B. TT, EVERI ENOCH, M. A., ZHOU, Z., KI MURA, M., MASH, D. MASH, M., MURA, KI Z., ZHOU, A., M. ENOCH, NC,M . CWRZ . LAG,B,V VI B., ALBAUGH, L., SCHWARTZ, A., M. ENOCH, ENOCH, M. A., HODGKI NSON, C. A., YUAN, Q., SHEN, P. SHEN, Q., YUAN, A., C. NSON, HODGKI A., M. ENOCH, ENOCH,M.A.2011. The role ofearly life stre ENOCH, M. A., HODGKI NSON, C. A., YUAN, Q., ALBAUGH, Q., YUAN, A., C. NSON, HODGKI A., M. ENOCH, ENOCH, M. A. 2008. The role of GABA(A) re GABA(A) of role The 2008. A. M. ENOCH, ENOCH, M. A., BAGHAL, B., YUAN, Q. & GOLDMAN, D. 20 D. GOLDMAN, & Q. YUAN, B., BAGHAL, A., M. ENOCH, FORD, M. M., NI CKEL, J. D., KAUFMAN, M. N. & FI NN, NN, FI & N. M. KAUFMAN, D., J. CKEL, NI M., M. FORD, EDENBERG, H. J., DI CK, D. M., XUEI , X., TI AN, H., A H., AN, TI X., , XUEI M., D. CK, DI J., H. EDENBERG, ENGI N, E., BAKHURI N, K. I ., SMI TH, K. S., HI NES, R. NES, HI S., K. TH, SMI ., I K. N, BAKHURI E., N, ENGI EHLERS, C. L., WALTER, N. A., DI CK, D. M., BUCK, K. BUCK, M., D. CK, DI A., N. WALTER, L., C. EHLERS, LY,D . R DA,D . ANIS .B,P ER PI B., J. S, DAUNAI P., D. EDMAN, FRI W., D. FLOYD, FI NN, D. A., ROBERTS, A. J. & CRABBE, J. C. 1 C. J. CRABBE, & J. A. ROBERTS, A., D. NN, FI FRAU, R., PI LLOLLA, G., BI NI , V., TAMBARO, S., DEVO S., TAMBARO, V., , NI BI G., LLOLLA, PI R., FRAU, FRI EDEL, P., KAHLE, K. T., ZHANG, J., HERTZ, N., PI N., HERTZ, J., ZHANG, T., K. KAHLE, P., EDEL, FRI DUKA, T., TOWNSHEND, J. M., COLLI ER, K. & ST & K. ER, COLLI M., J. TOWNSHEND, T., DUKA, FLORESCO, S. B., WEST, A. R., ASH, B., MOORE, H. & & H. MOORE, B., ASH, R., A. WEST, B., S. FLORESCO, extracellular concentrations of dopam ine ine dopam of concentrations extracellular alcohol dependence by subtype-specific analysis. analysis. subtype-specific by ati Confirm dependence 2006. alcohol A. , SZEGEDI & G. L. DT, SCHMI GABA(A) receptors. receptors. GABA(A) of their roles in drug addiction. addiction. drug in roles their of Neuropsychiatr Genet, Neuropsychiatr corresponding findings in alcohol-naive P and NP ra NP and P alco alcohol-naive from in pus findings hippocam ortem corresponding postm in expression gene anxiety m ediates linkage of GABR of linkage ediates m anxiety influence of GABRA2, childhood traum a, and their in their and a, dependence. traum cocaine childhood GABRA2, of influence erpyhpamacology, pred Neuropsychopharm independent as GABRA2 and GABRG1 2009. Biochem Behav, Biochem Psychopharm acology (Berl), acology Psychopharm gene expression in hum an brain identifies specifici identifies brain exposure. an cocaine hum in expression gene BEGLEI TER, H. 2004. Variations in GABRA2, en GABRA2, in Variations M. T, SCHUCKI 2004. H. J., TER, CE, BEGLEI RI T., CH, REI LI J., J., S. KWON, O'CONNOR, K., JONES, V., HESSELBROCK, A., GOATE, receptor, are associat ed with alcohol dependence an dependence alcohol with ed associat are receptor, 1563-72. 1563-72. Genet, erpyhpamacology, rece GABAA Neuropsychopharm of containing basis Neural alpha2 for 2014. U. RUDOLPH, & J. S. MOSS, R., selected quantitative trait loci associated with al with associated loci odels. m trait ouse m quantitative selected Exp Ther, Exp expressi and acology pharm 04 ogtr ehnlsl-d inistratio self-adm ethanol Long-term 2004. C57BL/ 6 m ice. beha ice. m 6 C57BL/ attenuates 5alpha-reductase reductase type I gene alters ethanol consum ption pa ption consum ethanol Genet, alters gene Behav I type reductase DUAN, J., KHANNA, A. R., BI SHOP, P. N., SHOKAT, K. K. SHOKAT, N., P. SHOP, BI R., A. KHANNA, J., DUAN, functions after m ultiple detoxifications in alcohol in detoxifications ultiple m after functions seizure-prone and -resistant m ice. ice. m -resistant and seizure-prone dopam ine neuron firing differ firing neuron ine dopam Nat Neurosci, Nat repeated adm inistration. inistration. adm repeated 74 311 , 705-14. 705-14. 6 45 , 1071-9. 1071-9. Psychoneuroendocrinology, , Addict Biol, Addict 90 968-73. 968-73. , 341-53. 341-53. PLoS One, PLoS , 95-104. 95-104. Nat Rev Neurosci, Rev Nat Biol Psychiatry, Biol 141B Psychopharm acology (Berl), acology Psychopharm 15 34 39 on of GABAA receptors in basolateral am ygdala. ygdala. am basolateral in receptors GABAA of on 214 , 8 599-607. 599-607. , entially regulates tonic and ph and tonic regulates entially , , , 185-99. 185-99. 1245-54. 1245-54. 1805-15. 1805-15. e64014. e64014. Neurosci Biobehav Rev, Biobehav Neurosci , 17-31. 17-31. vioral effects of D1-, but not D2-like receptor ago receptor D2-like not but D1-, of effects vioral Alcohol Clin Exp Res, Exp Clin Alcohol A2 haplotypes with alcoholism . . alcoholism with haplotypes A2 67 ceptors in the developm ent of alcoholism . . alcoholism of ent developm the in ceptors 6 ss as a predictor for alcohol and drug dependence. dependence. drug and alcohol for predictor a as ss , , 20-7. 20-7. 215-29. 215-29. RKKUNEN, M. & GOLDMAN, D. 2006. Dim ensional ensional Dim 2006. D. GOLDMAN, & M. RKKUNEN, 995. Neuroactive steroid sensitivity in withdrawal withdrawal in sensitivity steroid Neuroactive 995. C., YUAN, Q. & GOLDMAN, D. 2012. GABAergic GABAergic 2012. D. GOLDMAN, & Q. YUAN, C., 38 EPHENS, D. N. 2003. I m pairm ent in cognitive cognitive in ent pairm m I 2003. N. D. EPHENS, in the nucleus accum bens after acute and and acute after bens accum nucleus the in M., REYNOLDS, L. M., TANG, W., SPRENGEL, W., TANG, M., L. REYNOLDS, M., , ptors in the nucleus accum bens. bens. accum nucleus the in ptors 542-51. 542-51. TO, P. & BORTOLATO, M. 2013. I nhibition of of nhibition I 2013. M. BORTOLATO, & P. TO, n by cynom olgus m acaques alters the the alters acaques m olgus cynom by n ibitory them e: phasic and tonic activation of of activation tonic and phasic e: them ibitory J. & CRABBE, J. C. 2010. A com parison of of parison com A 2010. C. J. CRABBE, & J. coding the alpha 2 subunit of the GABA(A) GABA(A) the of subunit 2 alpha the coding GRACE, A. A. 2003. Afferent m odulation of of odulation m Afferent 2003. A. A. GRACE, ral to the dorsal striatum : devolving views views devolving : striatum dorsal the to ral LMASY, L., BAUER, L. O., CROWE, R. R., R., R. CROWE, O., L. BAUER, L., LMASY, SELLA, L. I ., BUHLER, E., SCHALLER, F., F., SCHALLER, E., BUHLER, ., I L. SELLA, RE, P. J., GRANT, K. A. & MCCOOL, B. A. A. B. MCCOOL, & A. K. GRANT, J., P. RE, on of association of the GABRA2 gene with with gene GABRA2 the of association of on Psychiatr Genet, Psychiatr 13. A factor analysis of global GABAergic GABAergic global of analysis factor A 13. H., GOLDMAN, D. & ROY, A. 2010. The The 2010. A. ROY, & D. GOLDMAN, H., HELESCU, I ., KLAWE, C., DAHMEN, N., N., DAHMEN, C., KLAWE, ., I HELESCU, ic inpatients. inpatients. ic ictors for alcoholism in two populations. populations. two in alcoholism for ictors ts. ts. cohol use phenotypes in hum ans and and ans hum in phenotypes use cohol D. A. 2015. Null m utation of 5alpha- of utation m Null 2015. A. D. ty in response to chronic alcohol and and alcohol chronic to response in ty B., VI RKKUNEN, M. & GOLDMAN, D. D. GOLDMAN, & M. RKKUNEN, VI B., 106 benzodiazepine reward: requirem ent ent requirem reward: benzodiazepine d with brain oscillations. oscillations. brain with d PLoS One, PLoS 37 nzodiazepine-induced decreases in in decreases nzodiazepine-induced tterns in a sex-dependent m anner. anner. m sex-dependent a in tterns 19 teraction on alcohol, heroin, and and heroin, alcohol, on teraction A., PORJESZ, B., FOROUD, T. & & T. FOROUD, B., PORJESZ, A., , , T. K., NURNBERGER, J. I ., JR., JR., ., I J. NURNBERGER, K., T. , , 202-8. 202-8. M. & MEDI NA, I . 2015. WNK1- 2015. . I NA, MEDI & M. 1946-54. 1946-54. , 410-5. 410-5. oisadccieadcs addicts; cocaine and holics asic dopam ine transm ission. ission. transm ine dopam asic 7 Alcohol Clin Exp Res, Exp Clin Alcohol 16 , e29369. e29369. , 9-17. 9-17. Am J Med Genet B B Genet Med J Am J Pharm acol acol Pharm J m u Hum J Am Pharm acol acol Pharm nists in in nists 27 ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This GREGER, V., KNOLL, J. H., WOOLF, E., GLATT, K., TYN K., GLATT, E., WOOLF, H., J. KNOLL, V., GREGER, GRAY, C. M. 1994. Synchronous oscillations in in oscillations Synchronous 1994. M. C. GRAY, GRABENSTATTER, H. L., DEL ANGEL, Y. C., CARLSEN, J. CARLSEN, C., Y. ANGEL, DEL L., H. GRABENSTATTER, OZLZ .I. RBNTTE,H . E-E IO, RI CEA-DEL L., H. GRABENSTATTER, ., I M. GONZALEZ, GRABENSTATTER, H. L., COGSWELL, M., CRUZ DE CRUZ M., COGSWELL, L., H. GRABENSTATTER, HART, A. S., RUTLEDGE, R. B., GLI MCHER, P. W. & & W. P. MCHER, GLI B., R. RUTLEDGE, S., A. HART, GONDRE-LEWI S, M. C., WARNOCK, K. T., WANG, H., JUNE H., WANG, T., K. WARNOCK, C., M. S, GONDRE-LEWI HAUGHEY, H. M., RAY, L. A., FI NAN, P., VI LLANUEVA, LLANUEVA, VI P., NAN, FI A., L. RAY, M., H. HAUGHEY, GOLDBERG, J. A., BORAUD, T., MARATON, S., HABER, S. HABER, S., MARATON, T., BORAUD, A., J. GOLDBERG, HANCHAR, H. J., CHUTSRI NOPKUN, P., MEERA, P., SUPAV P., MEERA, P., NOPKUN, CHUTSRI J., H. HANCHAR, GARRETT, K. M., HAQUE, D., BERRY, D., NI EKRASZ, EKRASZ, NI D., BERRY, D., HAQUE, M., K. GARRETT, GHOSH, S., BEGLEI TER, H., PORJESZ, B., CHORLI AN, D. AN, CHORLI B., PORJESZ, H., TER, BEGLEI S., GHOSH, HAMI D, A. A., PETTI BONE, J. R., MABROUK, O. S., HET S., O. MABROUK, R., J. BONE, PETTI A., A. D, HAMI F R I T Z ,B .M .& B O E H M ,S .L . ,2 N D2 0 1 4 .S i t e - s p e c i f i HALYBURTON, A. K., BRI NKWORTH, G. D., WI LSON, C. J. C. LSON, WI D., G. NKWORTH, BRI K., A. HALYBURTON, FRI TSCHY, J. M., PANZANELLI , P. & TYAGARAJAN, S. K. S. TYAGARAJAN, & P. , PANZANELLI M., J. TSCHY, FRI UN .G,CNINHM . ITHL,S . W NN SWI G., S. TCHELL, MI L., NGHAM, CUNNI G., B. GUNN, GROBI N, A. C., FRI TSCHY, J. M. & MORROW, A. A. MORROW, & M. J. TSCHY, FRI C., A. N, GROBI FRI TSCHY, J. M. & PANZANELLI , P. 2014. GAB 2014. P. , PANZANELLI & M. J. TSCHY, FRI (GABRA5) on hum an chrom osom e 15q11-q13 and and 15q11-q13 e ics, osom is Genom chrom an (GABRG3) hum gene on subunit (GABRA5) 3 1 a AL. m ET & gam Y. NAKATSU, M., receptor J. KELA, SI J., A. N, TOBI m odel of acquired epilepsy. subseque epilepsy. and acquired of epilepticus odel m status on 2 R. A. inhibition BROOKS-KAYAL, & J. S. RUSSEK, M., COGSWELL, Com put Neurosci, put Com RAOL, Y. H., RUSSEK, S. J. & BROOKS-KAYAL, BROOKS-KAYAL, & J. S. RUSSEK, H., Y. RAOL, on GABAA recept or alpha4 subunit expression in an a an in expression subunit epilepsy. alpha4 or recept GABAA on Seizure-related regulation of GABAA rece GABAA of regulation M M. HUNTSMAN, Seizure-related M., A. TE, WHI P., R. LAOPRASERT, J., Dis, is m ediated via a CRF/ GABA m echanism . . al echanism m excessive GABA CRF/ a for via factor ediated m risk is a is stress life H. Early LUDDENS, J., COOK, V., V. RUVEEDHULA, TI Neurosci, effects of alcohol and brain m RNA expression. alph expression. RNA m receptor A brain acid and alcohol of inobutyric a-am effects m gam an Hum 2008. in the rat nucleus accum bens sym m etrically encodes encodes etrically m sym bens accum nucleus rat the in 103 1,2,3,6-tetrahydropyridine prim ate m odel of Parkins of odel m ate prim neuro cortex otor m ary prim ong 1,2,3,6-tetrahydropyridine am synchrony Enhanced antagonist Ro15-4513 to alpha4/ 6beta3delta GABAA re GABAA 6beta3delta alpha4/ to petitive com and Ro15-4513 potently antagonist Ethanol 2006. W. R. OLSEN, 8-15. 8-15. GOATE, A. & REI CH, T. 2003. Linkage m apping of beta of apping m Linkage regression. 2003. T. CH, REI & A. GOATE, 2 subunit cluster on m ouse chrom osom e 11. 11. e osom chrom ouse m on (Gabra gene cluster subunit subunit 6 2 alpha receptor GABAA The the value of work. work. of value the C. M., KENNEDY, R. T., ARAGONA, B. J. & BE & J. B. ARAGONA, T., R. KENNEDY, M., C. nrlmbccre dltse ao naei ale m in intake hanol et odulates m cortex bic infralim effect s on m ood but not cognitive perform ance. ance. perform cognitive not but ood m high-carbohydrat on s and Low- effect 2007. M. P. FTON, CLI & B. heterogeneity of GABAergic synapses. synapses. GABAergic of heterogeneity 2015. GABAA receptor-acting neurosteroids: a a response. neurosteroids: stress the receptor-acting GABAA 2015. im m unoreactivity for GABA(A) receptor subunits Res, receptor Exp GABA(A) Clin for Alcohol unoreactivity m im action of GABA in im m ature neurons. neurons. ature m im in GABA of action regulated inhibitory phosphorylation of the K the of phosphorylation inhibitory regulated neurotransm ission in the central nervous system . . system nervous central the in ission neurotransm 77 , 8546-51. 8546-51. , 246-56. 246-56. 34 Epilepsia, 26 Am J Med Genet B Neuropsychiatr Genet, Neuropsychiatr B Genet Med J Am , 698-704. 698-704. , 258-64. 258-64. 1 Nat Neurosci, Nat 55 , 11-38. 11-38. Front Neuroendocrinol, Front 24 , 1826-33. 1826-33. , 1137-44. 1137-44. Neurobiol Dis, Neurobiol 19 , 117-26. 117-26. Sci Signal, Sci Cell Mol Life Sci, Life Mol Cell ernlsse : ech m s: system neuronal Stress, 62 ptors in spontaneously epileptic rats. rats. epileptic spontaneously in ptors L. 2000. Chronic ethanol adm inistration alters alters inistration adm ethanol Chronic 2000. L. 36 PHI LLI PS, P. E. 2014. Phasic dopam ine release release ine dopam Phasic 2014. E. P. PS, LLI PHI L ANGEL, Y., CARLSEN, J., GONZALEZ, M. I ., ., I M. GONZALEZ, J., CARLSEN, Y., ANGEL, L RKE, J. D. 2016. Mesolim bic dopam ine signals signals ine dopam bic Mesolim 2016. D. J. RKE, Brain Res Mol Brain Res, Brain Mol Res Brain , I ., GAN, J., ROTTER, A. & SEALE, T. W. 1997. 1997. W. T. SEALE, & A. ROTTER, J., GAN, ., I CC2 cotransporter m aintains the depolarizing depolarizing the aintains m cotransporter CC2 73-85. 73-85. AA receptors and plasticity of inhibitory inhibitory of plasticity and receptors AA Genes Brain Behav, Brain Genes DALE, R. F., DELOREY, T. M., OLSEN, R. W., W., R. OLSEN, M., T. DELOREY, F., R. DALE, , nt spontaneous seizures in the pilocarpine pilocarpine the in seizures spontaneous nt cohol drinking and im pulsivity in adults and and adults in pulsivity im and drinking cohol A. R. 2014a. Effect of of Effect 2014a. R. A. RI CK, V. L., SCHMI DT, R., VANDER WEELE, WEELE, VANDER R., DT, SCHMI L., V. CK, RI 28-48. 28-48. tightly linked to the alpha 5 subunit gene gene subunit 5 alpha the to linked tightly Am J Clin Nutr, Clin J Am 8 role in the developm ent and regulation of of regulation and ent developm the in role 19 , AURELI AN, L. & JUNE, H. L., SR. 2016. 2016. SR. L., H. JUNE, & L. AN, AURELI , in rat cortex in a region-specific m anner. anner. m region-specific a in cortex rat in R., NI CULESCU, M. & HUTCHI SON, K. E. E. K. SON, HUTCHI & M. CULESCU, NI R., , NOAKES, M., BUCKLEY, J. D., KEOGH, J. J. KEOGH, D., J. BUCKLEY, M., NOAKES, , 6) is tightly linked to the alpha 1-gamma 1-gamma alpha the to linked tightly is 6) Eur J Neurosci, J Eur , cm i c r o i n j e c t i o no fG a b o x a d o li n t ot h e I LAI , P., SI EGHART, W., WALLNER, M. & & M. WALLNER, W., EGHART, SI P., , LAI I C. A., CRUZ DEL ANGEL, Y., CARLSEN, CARLSEN, Y., ANGEL, DEL CRUZ A., C. ra65. ra65. N., VAADI A, E. & BERGMAN, H. 2002. 2002. H. BERGMAN, & E. A, VAADI N., Y, J. D., LAMBERT, J. J. & BELELLI , D. D. , BELELLI & J. J. LAMBERT, D., J. Y, C57BL/ 6J m ice. ice. m 6J C57BL/ , is transcribed in the sam e orientation. orientation. e sam the in transcribed is on's disease. disease. on's 235-247. 235-247. B., EDENBERG, H. J., FOROUD, T., T., FOROUD, J., H. EDENBERG, B., 118B , H. L., JR., BELL, K. A., RABE, H., H., RABE, A., K. BELL, JR., L., H. , 69 995. The gam m a-am inobutyric acid acid inobutyric a-am m gam The 995. , WEMPE, M. F., WHI TE, A. M., M., A. TE, WHI F., M. WEMPE, , 2012. Molecular and functional functional and Molecular 2012. ceptors. ceptors. a reward prediction error term . . term error prediction reward a 2 EEG waves via non-param etric etric non-param via waves EEG 2 ly inhibits binding of the alcohol alcohol the of binding inhibits ly e weight-loss diets have sim ilar ilar sim have diets weight-loss e , 2485-99. 2485-99. , nim al m odel of tem poral lobe lobe poral tem of odel m al nim 66-71. 66-71. a2 gene m oderates the acute acute the oderates m gene a2 . & BROOKS-KAYAL, A. 2015. 2015. A. BROOKS-KAYAL, & . si h - ethyl-4-phenyl- 1-m the in ns 014b. The effect of STAT3 STAT3 of effect The 014b. 86 39 Proc Natl Acad Sci U S A, S U Sci Acad Natl Proc J Neurosci, J 7 , anism s and functions. functions. and s anism 580-7. 580-7. , , Behav Brain Res, Brain Behav 447-54. 447-54. 1845-65. 1845-65. 45 spontaneous seizures seizures spontaneous , 133-7. 133-7. 22 , 4639-53. 4639-53. Neurobiol Neurobiol 273 J J ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This HSU, F. C., ZHANG, G. J., RAOL, Y. S., VALENTI NO, R. NO, VALENTI S., Y. RAOL, J., G. ZHANG, C., F. HSU, OE,V,GOG,P . UTIT . AIDS DAVI S., T, TOI DU M., P. GEORGE, V., HOMER, HODGE, C. W., CHAPPELLE, A. M. & SAMSON, H. H. SAMSON, & M. CHAPPELLE,A. W., C. HODGE, HERBERG, L. J., STEPHENS, D. N. & FRANKLI N, K. N, FRANKLI & N. D. STEPHENS, J., L. HERBERG, HERD, M. B., BROWN, A. R., LAMBERT, J. J. & BELELLI & J. J. LAMBERT, R., A. BROWN, B., M. HERD, ICS .A,BILY .E,R E,B . APU S KAMPHUI P., B. LEY, RI E., M. LEY, BAI A., A. CKS, HI HERMAN, M. A., KALLUPI , M., LUU, G., OLEATA, C. S., C. OLEATA, G., LUU, M., , KALLUPI A., M. HERMAN, HERRI NG, D., HUANG, R., SI NGH, M., ROBI NSON, NSON, ROBI M., NGH, SI R., HUANG, D., NG, HERRI HERBERG, L. J., MONTGOMERY, A. M., FI LE, S. E., PEL E., S. LE, FI M., A. MONTGOMERY, J., L. HERBERG, HEMBY, S. E., O'CONNOR J, A., ACOSTA, G., FLOYD, D. FLOYD, G., ACOSTA, A., J, O'CONNOR E., S. HEMBY, I NVERNI ZZI , R., POZZI , L. & SAMANI N, R. 1991. Relea 1991. R. N, SAMANI & L. , POZZI R., , ZZI NVERNI I I WATA, N., COWLEY, D. S., RADEL, M., ROY-BYRN M., RADEL, S., D. COWLEY, N., WATA, I HAYES, D. J., JUPP, B., SAWI AK, S. J., MERLO, J., S. AK, SAWI JUPP,B., J., D. HAYES, HEI MAN, M., SCHAEFER, A., GONG, S., PETERSON, J. D. J. PETERSON, S., GONG, A., SCHAEFER, M., MAN, HEI HEI TZEG, M. M., VI LLAFUERTE, S., WEI LAND, B. J., EN J., B. LAND, WEI S., LLAFUERTE, VI M., M. TZEG, HEI JANSSEN, M. J., ADE, K. K., FU, Z. & VI CI NI , S. 200 S. , NI CI VI & Z. FU, K., K. ADE, J., M. JANSSEN, JANAK, P. H., REDFERN, J. E. & SAMSON, H. H. 19 H. H. SAMSON, & E. J. REDFERN, H., P. JANAK, JENSEN, M. L., WAFFORD, K. A., BROWN, A. R., BELELL R., A. BROWN, A., K. WAFFORD, L., M. JENSEN, HU, X., OROSZI , G., CHUN, J., SMI TH, T. L., GOLDMAN L., T. TH, SMI J., CHUN, G., , OROSZI X., HU, JANAK, P. H. & MI CHAEL GI LL, T. 2003. Com parison of parison Com 2003. T. LL, GI CHAEL MI & H. P. JANAK, hippocam pal GABAA receptors and behavioral stress r stress sepa behavioral and aternal m receptors with GABAA pal handling hippocam neonatal Repeated 2003. hypobetalipoproteinem ia. ia. Disease: APOB. bol: sym Gene hypobetalipoproteinem utations. m pathological 100 accum bens is involved in the term ination of ethanol of ination term the in involved is bens accum Exp Res, Exp 84. 84. couple presynaptic activity to postsynaptic postsynaptic to activity presynaptic couple genes: localization of the alpha 6-subunit ge 6-subunit analysis. alpha the clusteri of linkage for evidence localization Further genes: 1994. G. M. SON, DARLI am ygdala of genetically selected Marchigian Sardini Marchigian acology, selected Neuropharm genetically of tran ygdala GABAergic am Enhanced 2013. M. ROBERTO, & Neurosci, m RNAs in prefrontal fields of cynom olgus m onkeys. onkeys. m olgus cynom of r fields Ethanol-induced prefrontal in RNAs 2006. m A. K. GRANT, & D. EDMAN, FRI 39 receptor antagonist) and ZK 91 296 (a putative part putative (a 296 91 beta-car ZK and novel the of antagonist) ulation receptor self-stim ic hypothalam evidence suggesting a reinforcing role for noradren for role ine. reinforcing dopam a suggesting evidence 278 dileucine AP2 adaptin-binding m otif within the beta the within otif dy m is endocytosis adaptin-binding AP2 receptor GABAA dileucine Constitutive 2003. m ore in the nucleus accum bens than in the caudate n caudate the in than acology, bens accum Neuropharm nucleus the in ore m HEI NTZ, N. 2008. A translational profiling approach profiling ypes. t cell CNS translational A 2008. ER, N. SURMEI NTZ, A., HEI D. STEPHAN, C., SCHWARZ, M., NAS, FARI Motivation Circuitry in a Sam ple Enriched for Alcoh for Enriched ple Sam a in Circuitry Motivation K .& Z U C K E R ,R .A .2 0 1 4 .E f f e c to fG A B R A 2G e n o t y p e A study of subunit selectivity, m echanism and site site and echanism m selectivity, subunit of study A conductance in striatal output neurons. neurons. output striatal in conductance AAri gnsso tao efaministrat self-adm ethanol on agonists GABAergic between a GABAA alpha 6 Pro385Ser substitu ry, Pro385Ser Psychiat 6 alpha GABAA a between evaluation of the relationship of four alleles to t to alleles four risk. of alcoholism relationship the of evaluation a -miouyi cd angetdrl ni puls im in role neglected a acid: inobutyric a-am m gam by the endogenous neuros endogenous the by sucrose. sucrose. , 3077-86. 3077-86. , , 12213-8. 12213-8. 24046-52. 24046-52. 19 Alcohol, 33 156 Pharm acol Biochem Behav, Biochem acol Pharm , , 1486-93. 1486-93. 14850-68. 14850-68. , Cell, 1447-9. 1447-9. Alcohol Clin Exp Res, Exp Clin Alcohol 30 eo ics, Genom 135 , 67 30 1-7. 1-7. , , , 337-48. 337-48. 575-8. 575-8. 738-48. 738-48. Hum Genet, Hum teroid, allopr teroid, 20 , 285-8. 285-8. 29 121 4 egnanolone. egnanolone. J Neurosci, J , , 575-82. 575-82. 8-16. 8-16. E., CAPRI OLI , D. & DALLEY, J. W. 2014. Brain Brain 2014. W. J. DALLEY, & D. , OLI CAPRI E., , H. 1995. GABAergic transm ission in the nucleus nucleus the in ission transm GABAergic 1995. H. 98. The reinforcing effects of ethanol are altered altered are ethanol of effects reinforcing The 98. 645-6. 645-6. ON, J. S. & WI LSON, C. J. 2007. Novel hum an an hum Novel 2007. J. C. LSON, WI & S. J. ON, B 96 aehlmines Catecholam 1976. B. L. C., DI LLON, G. H. & LEI DENHEI MER, N. J. J. N. MER, DENHEI LEI & H. G. LLON, DI C., L. E, P. P. & GOLDMAN, D. 1999. Relationship Relationship 1999. D. GOLDMAN, & P. P. E, inhibition in the som atosensory thalam us. us. thalam atosensory som the in inhibition J., COULTER, D. A. & BROOKS-KAYAL, A. R. R. A. BROOKS-KAYAL, & A. D. COULTER, J., HEI LI G, M., KOOB, G. F., CI CCOCI OPPO, R. R. OPPO, CCOCI CI F., G. KOOB, M., G, LI HEI LOW, S. & STEPHENS, D. N. 1986. Effect on on Effect 1986. N. D. STEPHENS, & S. LOW, ne (GABRA6) to distal chromosome 5q by , D. 2013. Extrasynaptic GABA(A) receptors receptors GABA(A) Extrasynaptic 2013. D. , , D. & SCHUCKI T, M. A. 2005. An expanded expanded An 2005. A. M. T, SCHUCKI & D. , , W., SI CI LI ANO, M. J., JOHNSON, K. J. & & J. K. JOHNSON, J., M. ANO, LI CI SI W., , ion with and without co without and with ion the effects of allopregnanolone with direct direct with allopregnanolone of effects the OCH, M. A., BURMEI STER, M., ZUBI ETA, J. J. ETA, ZUBI M., STER, BURMEI A., M. OCH, tion and benzodiazepine sensitivity. sensitivity. benzodiazepine and tion I , D., LAMBERT, J. J. & MI RZA, N. R. 2013. 2013. R. N. RZA, MI & J. J. LAMBERT, D., , I eo oa n srdcdb izpmdiazepam by reduced is ine dopam of se 9. Dopam ine m odulation of GABA tonic tonic GABA of odulation m ine Dopam 9. he level of response to alcohol and the the and alcohol to response of level he 29 sm ission in the central nucleus of the the of nucleus central the in ission sm 2 subunit of the receptor. receptor. the of subunit 2 self-adm inistration in rats. rats. in inistration self-adm olism Risk. Risk. olism Alcohol Clin Exp Res, Exp Clin Alcohol Alcohol Clin Exp Res, Exp Clin Alcohol , DAY, M., RAMSEY, K. E., SUAREZ- E., K. RAMSEY, M., DAY, , bolines ZK 93 426 (a benzodiazepine benzodiazepine (a 426 93 ZK bolines for the m olecular characterization of of characterization olecular m the for ial agonist). agonist). ial ivity. ivity. ng of hum an GABAA receptor subunit subunit receptor GABAA an hum of ng nam in-m ediated and dependent on a a on dependent and ediated in-m nam , , ANDERSON, N., MCCOOL, B. A., A., B. MCCOOL, N., ANDERSON, , 5116-26. 5116-26. esponses. esponses. an rats: alcohol and CRF effects. CRFeffects. and alcohol rats: an aline and a m otivating role for for role otivating m a and aline of action of the delta selective selective delta the of action of Eur J Neurosci, J Eur o nD e v e l o p m e n to fI n c e n t i v e - egulation of GABA-A subunit subunit GABA-A of egulation D. J., GREENGARD, P. & & P. GREENGARD, J., D. ration perm anently alters alters anently perm ration ucleus of conscious rats. rats. conscious of ucleus erpyhpamacology, Neuropsychopharm Proc Natl Acad Sci U S A, S U Sci Acad Natl Proc erlTas , Transm Neural J norm otriglyceridem ic ic otriglyceridem norm adsl-tmuain ulation: self-stim and ncurrently available available ncurrently 22 30 39 , , 1106-12. 1106-12. 1978-85. 1978-85. , 1921-32. 1921-32. ilCe , Chem Biol J Alcohol Clin Clin Alcohol 66 Am J Am , 75- J

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This KELLEY, A. E. & DELFS, J. M. 1991b. Dopam ine and co and ine Dopam 1991b. M. J. DELFS, & E. A. KELLEY, KELLEY, A. E. & DELFS, J. M. 1991a. Dopam ine ine Dopam 1991a. M. J. DELFS, & E. A. KELLEY, KHI STI , R. T., BOYD, K. N., KUMAR, S. & MORROW, A. A. MORROW, & S. KUMAR, N., K. BOYD, T., R. , STI KHI KERTES, D. A., KALSI , G., PRESCOTT, C. A., KUO, P. P. KUO, A., C. PRESCOTT, G., , KALSI A., D. KERTES, AEE,D . IAG . EHR L . ZM Z C DZI DZEMI L., LL, WETHERI T., ANG, LI A., D. KAREKEN, KORPI , E. R., DEBUS, F., LI NDEN, A. M., MALECOT, C. MALECOT, M., A. NDEN, LI F., DEBUS, R., E. , KORPI KALK, N. J., MELI CHAR, J., HOLMES, R. B., TAYLOR, L TAYLOR, B., R. HOLMES, J., CHAR, MELI J., N. KALK, KOOB, G. F. & VOLKOW, N. D. 2010. Neurocircuitry of Neurocircuitry 2010. D. N. VOLKOW, & F. G. KOOB, KI TTLER, J. T. & MOSS, S. J. 2003. Modulation of GA of Modulation 2003. J. S. MOSS, & T. J. TTLER, KI KOOS, T. & TEPPER, J. M. 1999. I nhibitory control o control nhibitory I 1999. TEPPER,M. J. & T. KOOS, KAI LA, K., RUUSUVUORI , E., SEJA, P., VOI PI O, J. & P & J. O, PI VOI P., SEJA, E., , RUUSUVUORI K., LA, KAI J K. STALEY, J., DUAN, R., A. KHANNA, T., K. KAHLE, KI RSTEI N, S. L., DAVI DSON, K. L., EHRI NGER, M. A., A., M. NGER, EHRI L., K. DSON, DAVI L., S. N, RSTEI KI JUNE, H. L., SR., FOSTER, K. L., EI LER, W. J., 2ND, J., W. LER, EI L., K. FOSTER, SR., L., H. JUNE, KI M, Y. S., YANG, M., MAT, W. K., TSANG, S. Y., SU, Y., S. TSANG, K., W. MAT, M., YANG, S., Y. M, KI ONO,A . ADAE,R . UIT .L,N Z NI L., S. T, PULI E., R. HANDSAKER, D., A. JOHNSON, JOHNSON, K. J., SANDER, T., HI CKS, A. A., VAN MARLE VAN A., A. CKS, HI T., SANDER, J., K. JOHNSON, JI N, Z., BHANDAGE, A. K., BAZOV, I ., KONONENKO, O., KONONENKO, ., I BAZOV, K., A. BHANDAGE, Z., N, JI JI AO, D. L., LI U, Y., LONG, J. D., DU, J., JU, Y. Y Y. JU, J., DU, D., J. LONG, Y., U, LI L., D. AO, JI 2169-78. 2169-78. m icroinjection into the ventral tegm ental area. area. ental tegm nucl the ventral into the into icroinjection m ine icroinjection m phetam am of effects elevates deoxycort icosterone levels and ch and levels response. icosterone deoxycort elevates associated with a history of depressive sym ptom s in s ptom sym Res, depressive Exp of Clin Alcohol history a with Ne associated 2011. P. B. LEY, RI & S. K. KENDLER, the m edial frontal response to alcohol cues in an f an in cues alcohol to response orphi frontal polym A edial m 2010. the T. FOROUD, & J. S. O'CONNOR, T., (Berl), effects of am phetam ine m icroinjections into striata into icroinjections m ine phetam am of effects preferentially via selected brain GABAA receptor su receptor GABAA brain biguous. selected am via W. SDEN, preferentially WI ., I M. ALLER, ., I BOHME, Single Photon Em ission Com puted Tom ography study. study. ography Tom challen puted Com clonidine ission a Em to Photon Single responsiveness NUTT & R. A. noradrenergic NGFORD-HUGHES, LI A., TH, LENNOX-SMI T., 13 receptor trafficking: im plications for for plications im trafficking: receptor interneurons. interneurons. 217-38. 217-38. Cotransporter and Hum an Epilepsy: Getting Excited A Excited Getting Epilepsy: an Hum and Cotransporter plasticity in epilepsy. epilepsy. in plasticity ethanol-induced ataxia and brain cAMP signaling in in sen signaling cAMPTher, Exp initial brain acol and Pharm affecting ataxia loci trait ethanol-induced Quantitative 2002. enhanced locom otor stim ulation in the GABAA alpha1 alpha1 GABAA the acology, in ulation Neuropsychopharm stim otor locom benzodiazepine-d and enhanced ine Y JR., Dopam L., H. 2007. JUNE, E. G. O., J. MMONS, SI B., MENSAH-ZOE, Association with Heroin Depend XU Heroin & W. with HAO, X., CHEN, Association J., TANG, Y., AO, LI F., PUN, com pound 2 (DS2) at hum an recom binant binant recom an hum at (DS2) 2 pound com alpha 1-subunit gene (GABRA1) to distal 5q by linka by 5q distal to localiz the (GABRA1) of gene ation 1-subunit Confirm alpha 1992. G. M. SON, DARLI & BAKKER, P. I . 2008. SNAP: a web-based tool for iden for tool HapMap. using web-based SNPs a SNAP: 2008. . I P. BAKKER, decreased in central am ygdala of alcoholics. alcoholics. of ygdala am central in decreased 2 0 1 4 .E x p r e s s i o no fs p e c i f i ci o n o t r o p i cg l u t a m a t ea hr acol, Pharm I nvolvem ent of dorsal striatal alpha1-con rewa ed striatal associat dorsal of ent nvolvem I , 341-7. 341-7. 103 Brain Res, Brain , 168 187-96. 187-96. Alcohol, Nat Neurosci, Nat , rding m em ories. ories. em m rding 1118-32. 1118-32. 41 1049 302 35 iifr atics, Bioinform Curr Opin Neurobiol, Opin Curr , 163-76. 163-76. , 496-505. 496-505. , 1238-45. 1238-45. , 104-11. 104-11. 2 32 , 467-72. 467-72. , 137-52. 137-52. ence in Chinese Population. Population. Chinese in ence Neuroscience, 24 the efficacy of synaptic inhibition. inhibition. synaptic of efficacy the , 2938-9. 2938-9. 26 ann AA eetr nmehmpea ine- phetam etham m in receptors GABAA taining & LUDDENS, H. 2007. Does ethanol act act ethanol Does 2007. H. LUDDENS, & and conditioned reinforcem ent. I . Differential Differential . I ent. reinforcem conditioned and Front Cell Neurosci, Cell Front f neostriatal projection neurons by GABAergic GABAergic by neurons projection neostriatal f ., ZAN, G. Y., LI U, J. G. & ZHAO, M. 2016. 2016. M. ZHAO, & G. J. U, LI Y., G. ZAN, ., , ., DELPI RE, E. & PODURI , A. 2016. The KCC2 KCC2 The 2016. A. , PODURI & E. RE, DELPI ., BAA receptor activity by phosphorylation and and phosphorylation by activity receptor BAA 34-41. 34-41. and rodent native GABA(A) receptors. receptors. GABA(A) native rodent and USKARJOV, M. 2014. GABA actions and ionic ionic and actions GABA 2014. M. USKARJOV, SI KELA, J. M., ERWI N, V. G. & TABAKOFF, B. B. TABAKOFF, & G. V. N, ERWI M., J. KELA, SI . G., DAGLI SH, M. R., HOOD, S., EDWARDS, EDWARDS, S., HOOD, R., M. SH, DAGLI G., . GOERGEN, J., COOK, J. B., JOHNSON, N., N., JOHNSON, B., J. COOK, J., GOERGEN, urotransm itter and neurom odulator genes genes odulator neurom and itter urotransm 320 Psychopharm acology (Berl), acology Psychopharm ependent m echanism s regulate the EtOH- the regulate s echanism m ependent , LEPPA, E., VEKOVI SCHEVA, O., RABE, H., H., RABE, O., SCHEVA, VEKOVI E., LEPPA, , Z., JI ANG, X., NG, S. K., LI U, S., HU, T., T., HU, S., U, LI K., S. NG, X., ANG, JI Z., ronic ethanol exposure ethanol ronic addiction. addiction. , A., JANZ, D., MULLAN, M. J., RI LEY, B. P. P. B. LEY, RI J., M. MULLAN, D., JANZ, A., , BAKALKI N, G., KORPI , E. R. & BI RNI R, B. B. R, RNI BI & R. E. , KORPI G., N, BAKALKI , M., BRAGULAT, V., COX, C., TALAVAGE, TALAVAGE, C., COX, V., BRAGULAT, M., , sitivity and acute functional tolerance to to tolerance functional acute and sitivity L. 2005. System ic ethanol adm inistration inistration adm ethanol ic System 2005. L. nditioned reinforcem ent. I I . Contrasting Contrasting . I I ent. reinforcem nditioned , ZARI , M. M., O'DONNELL, C. J. & DE DE & J. C. O'DONNELL, M., M. , ZARI 230-8. 230-8. ge analysis. analysis. ge H., PATTERSON, D. G., WALSH, D., D., WALSH, G., D. PATTERSON, H., ge in Generalized Anxiety Disorder: a a Disorder: Anxiety Generalized in ge MRI study. study. MRI individuals with alcohol dependence. dependence. alcohol with individuals bout I nhibition. nhibition. I bout ation of the hum an GABAA receptor receptor GABAA an hum the of ation scohr acol, Psychopharm J l subregions. subregions. l I N, W., COOK, J. M. & HOMANI CS, CS, HOMANI & M. J. COOK, W., N, I n dG A B A - Ar e c e p t o rs u b u n i t si s btypes? the current evidence is is evidence current the btypes? BXD recom binant inbred m ice. ice. m inbred binant recom BXD tification and annotation of proxy proxy of annotation and tification sm in GABRA2 is associated with with associated is GABRA2 in sm E, H. 2015. GABRB2 Haplotype Haplotype GABRB2 2015. H. E, eus accum bens with peptide peptide with bens accum eus erpyhpamacology, Neuropsychopharm PLoS One, PLoS subunit null m utant m ice. ice. m utant m null subunit 8 eo ics, Genom Alcohol Clin Exp Res, Exp Clin Alcohol , , D. J. 2012. Central Central 2012. J. D. , 288. 288. Neuroscientist 10 Psychopharm acology acology Psychopharm Curr Opin Neurobiol, Opin Curr attenuat es this this es attenuat , e0142049. e0142049. 26 14 103 , 452-60. 452-60. , 745-8. 745-8. , 197-203. 197-203. . . 34 Br J Br 35 J , ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This LI EBMAN, J. M. 1985. Anxiet y, anxiolyt y, Anxiet 1985. M. J. EBMAN, LI IEEMN . RNLR .R,JSI,P,SIN SHI P., , JOSHI R., H. KRANZLER, R., EBERMAN, LI LI ANG, J., LI NDEMEYER, A. K., SURYANARAYANAN, A., M A., SURYANARAYANAN, K., A. NDEMEYER, LI J., ANG, LI LI , D., SULOVARI , A., CHENG, C., ZHAO, H., KRANZLER H., ZHAO, C., CHENG, A., , SULOVARI D., , LI LEVRAN, O., PELES, E., RANDESI , M., CORREA DA ROSA, CORREADA M., , RANDESI E., PELES, O., LEVRAN, LE MERRER, J. & STEPHENS, D. N. 2006. Food-induced Food-induced 2006. N. D. STEPHENS, & J. MERRER, LE LEES, R., KI NGSTON, R., WI LLI AMS, T. M., HENDERSON, M., T. AMS, LLI WI R., NGSTON, KI R., LEES, LEE, H. H., JURD, R. & MOSS, S. J. 2010. Ty 2010. J. S. MOSS, & R. JURD, H., H. LEE, LAURI E, D. J., WI SDEN, W. & SEEBURG, P. H. 1992. Th 1992. H. P. SEEBURG, & W. SDEN, WI J., D. E, LAURI LOH, E. W., HI GUCHI , S., MATSUSHI TA, S., MURRAY, R. MURRAY, S., TA, MATSUSHI S., , GUCHI HI W., E. LOH, LI NGFORD-HUGHES, A., MYERS, J., WATSON, B., REI D, A D, REI B., WATSON, J., MYERS, A., NGFORD-HUGHES, LI LI NGFORD-HUGHES, A., REI D, A. G., MYERS, J., FEENEY J., MYERS, G., A. D, REI A., NGFORD-HUGHES, LI LAPPALAI NEN, J., KRUPI TSKY, E., REMI ZOV, M., PCHELI M., ZOV, REMI E., TSKY, KRUPI J., NEN, LAPPALAI LAMBERT, J. L. 2013. Stress exposure during ea during exposure Stress 2013. L. J. LAMBERT, LI NDEN, A. M., SCHMI TT, U., LEPPA, E., WULFF, P., W P., WULFF, E., LEPPA, U., TT, SCHMI M., A. NDEN, LI KUMAR, S., PORCU, P., WERNER, D. F., MATTHEWS, D. B D. MATTHEWS, F., D. WERNER, P., PORCU, S., KUMAR, KUPCHI K, Y. M., BROWN, R. M., HEI NSBROEK, J. A., LO A., J. NSBROEK, HEI M., R. BROWN, M., Y. K, KUPCHI LI NDEMEYER, A. K., LI ANG, J., MARTY, V. N., MEYER, N., V. MARTY, J., ANG, LI K., A. NDEMEYER, LI KRETSCHMANNOVA, K., HI NES, R. M., REVI LLA-SANCHEZ, LLA-SANCHEZ, REVI M., R. NES, HI K., KRETSCHMANNOVA, dae ertas sini h ulu cu bens accum nucleus the in ission Neurophysiol, 2014. . I neurotransm GELMAN, SPI & ediated W. m R. OLSEN, M., X. SHAO, O., Rev, GABAA Subunit Genes in Hum an Neural Cultures. Cultures. Neural an Hum in Genes with Subunit Associated GABAA is Allele Risk Dependence of gam m a-am inobutyric acid A receptor alpha2 gene ( gene alpha2 acology, receptor A acid Neuropsychopharm inobutyric a-am m gam of cocaine addiction in subjects of African and Europe and African of su subjects GABAergic in and addiction atergic cocaine Glutam 2016. J. M. KREEK, & Neuropsychopharm acol Biol Psychiatry, Biol acol Neuropsychopharm 4151-72. 4151-72. estzto occieadmopie hr acologi pharm orphine, m and intake. cocaine to sensitization Alcohol Alcohol, Alcohol M. 2012. Com parison of ethyl glucuronide in hair wi hair in glucuronide ethyl of parison Com 2012. M. trafficking of the potassium chloride co-transporte chloride potassium the of trafficking subunit m RNAs in the rat brain. I I I . Em bryonic and and bryonic Em . I I I brain. rat the in RNAs m subunit 81. 81. dependence in a Japanese population. population. Japanese a in GA the dependence of analysis Association ezdaeiercposi paeadcin addiction: opiate in 45 Ro15 receptors C] [ Using benzodiazepine 2016. J. TAYLOR, D. J., NUTT, C. & TY, F. MER, NNI TURKHEI MCGI A., D. ANO-BARROS, RI A., eri age, Neuroim reduced alpha5 benzodiazepine receptors in lim bic r bic lim in depe receptors alcohol benzodiazepine that alpha5 suggests reduced PETstudy 4513 Ro15 P GRASBY, 11C] J., [ D. BROOKS, F., MER, TURKHEI L., ROSSO, Association between alcoholism and gam m a-am ino buty ino a-am m gam and population. Russian a alcoholism between KRYST R., H. Association KRANZLER, J., COVAULT, K., L. SOMBERG, 2011. Ro 15-4513 Antagonizes Alcohol- Antagonizes 15-4513 Ro 2011. alphabetagam m a2-type GABA( A) Receptors. Receptors. A) GABA( a2-type m alphabetagam Neurosci, hr acology, Pharm of ethanol: a decade of progress. progress. of decade a GABA(A of role ethanol: The of 2009. L. A. MORROW, & S. W. 2015. Coding the direct/ indirect pathways by D1 D1 by pathways indirect projections. bens direct/ accum the Coding 2015. W. function in adulthood, resulting in senstized respo senstized in resulting adulthood, in function & SPI GELMAN, I . 2014. Ethanol-induced plastici ygdala. am Ethanol-induced 2014. . I GELMAN, SPI & the hypnotic and am nestic actions of the in the of actions nestic am and A. P. ES, hypnotic DAVI & J. the S. MOSS, B., M. KELZ, R., 9 , 75-86. 75-86. J Neurosci, J 33 Neurochem Res, Neurochem , 132 7264-73. 7264-73. 112 24 47 , , 1-7. 1-7. , 26 e7. e7. 39-50. 39-50. , 267-72. 267-72. , Alcohol Clin Exp Res, Exp Clin Alcohol 7163-71. 7163-71. Nat Neurosci, Nat 39 39 BA(A) receptor subunit genes cl genes subunit receptor BA(A) , , 1162-70. 1162-70. 907-18. 907-18. ics and brain stim ulation reinforcem ent. ent. reinforcem ulation stim brain and ics Psychopharm acology (Berl), acology Psychopharm 18 o scitry, Psychiat Mol 64 rly developm ent alters accum bens GABAA receptor receptor GABAA bens accum alters ent developm rly , rosine phosphorylation regulates the m em brane brane em m the regulates phosphorylation rosine 1230-2. 1230-2. , 29 travenous anesthetics etom idate and propofol. propofol. and idate etom anesthetics travenous 118-23. 118-23. , D. G. & COVAULT, J. 2015. GABRA2 Alcohol Alcohol GABRA2 2015. J. COVAULT, & G. D. , Reduced Expression of Chrom osom e 4p12 4p12 e osom Chrom of Expression Reduced Front Neurosci, Front , E. M., SURYANARAYANAN, A., OLSEN, R. W. W. R. OLSEN, A., SURYANARAYANAN, M., E. Sim ilarities and differ and ilarities Sim 493-8. 493-8. 2013. Enhanced tonic inhibition influences influences inhibition tonic Enhanced 2013. ) receptors in the acute and chronic effects effects chronic and acute the in receptors ) BO, M. K., SCHWARTZ, D. J. & KALI VAS, P. P. VAS, KALI & J. D. SCHWARTZ, K., M. BO, , H. R. & GELERNTER, J. 2014. Association Association 2014. J. GELERNTER, & R. H. , I nduced Sedation Sedation nduced I I SDEN, W., LUDDENS, H. & KORPI , E. R. R. E. , KORPI & H. LUDDENS, W., SDEN, I ty of GABAA receptors in the basolateral basolateral the in receptors GABAA of ty e distribution of thirteen GABAA receptor receptor GABAA thirteen of distribution e J., OTT, J., ROTROSEN, J., ADELSON, M. M. ADELSON, J., ROTROSEN, J., OTT, J., G., LI NGFORD-HUGHES, A. & HI CKMAN, CKMAN, HI & A. NGFORD-HUGHES, LI G., Alcohol Clin Exp Res, Exp Clin Alcohol r KCC2. KCC2. r ., DI AZ-GRANADOS, J. L., HELFAND, R. R. HELFAND, L., J. AZ-GRANADOS, DI ., EYER, E. M., MARTY, V. N., AHMAD, S. S. AHMAD, N., V. MARTY, M., E. EYER, NA, S., TARASKI NA, A., ZVARTAU, E., E., ZVARTAU, A., NA, TARASKI S., NA, . G., KALK, N., FEENEY, A., HAMMERS, HAMMERS, FEENEY,A., N., KALK, G., . R., TERUNUMA, M., TRETTER, V., JURD, JURD, V., TRETTER, M., TERUNUMA, R., postnatal developm ent. ent. developm postnatal , A., HAMMERS, A., TAYLOR, L. G., G., L. TAYLOR, A., HAMMERS, A., , th self-reported alcohol consum ption. ption. consum alcohol self-reported th egions. egions. 5 , CHEN, C. K. & BALL, D. 2000a. 2000a. D. BALL, & K. C. CHEN, , behavioral sensitization, its cross- its sensitization, behavioral GABRA2) with alcohol use disorder. disorder. use alcohol with GABRA2) , cal blockade, and effect on food food on effect and blockade, cal and D2 receptors is not valid for for valid not is receptors D2 and 301-7. 301-7. ric acid alpha2 receptor subtype in in subtype receptor alpha2 acid ric ndence in m an is associated with with associated is an m in ndence L. G., ROSSO, L., BROOKS, D. J., J., D. BROOKS, L., ROSSO, G., L. AL, J. H. & GELERNTER, J. 2005. 2005. J. GELERNTER, & H. J. AL, Mol Cell Neurosci, Cell Mol nses to cocaine. cocaine. to nses Plasticity of GABA(A) receptor- GABA(A) of Plasticity of alcohol-dependent rats. rats. alcohol-dependent of sceptibility loci for heroin and and heroin for loci sceptibility 13 PET to characterise GABA- characterise PETto 13 5 scohr acol, Psychopharm J ust er on 5q33-34 and alcohol alcohol and 5q33-34 on er ust 205 , 3. 3. . & NUTT, D. J. 2012. A A 2012. J. D. NUTT, & . , 529-64. 529-64. ences with alcoholism . . alcoholism with ences an ancestry. ancestry. an 39 in Mice Through Through Mice in Neurosci Biobehav Biobehav Neurosci , 1654-64. 1654-64. 45 J Neurosci, J , Behavioural Behavioural 173-9. 173-9. 26 , 273- Prog Prog 12 J J ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This MAROWSKY, A., RUDOLPH, U., FRI TSCHY, J. M. & AR & M. J. TSCHY, FRI U., RUDOLPH, A., MAROWSKY, MACPHERSON, T., DI XON, C. I ., JANAK, P. H., BELELLI H., P. JANAK, ., I C. XON, DI T., MACPHERSON, ATES .G,HFMN .K,ZZA . T FFLE STI N., ZEZZA, K., E. HOFFMAN, G., A. MATTHEWS, MAMELI , M., HALBOUT, B., CRETON, C., ENGBLOM, D., P D., ENGBLOM, C., CRETON, B., HALBOUT, M., , MAMELI LYDALL, G. J., SAI NI , J., RUPARELI A, K., MONTAGNESE K., A, RUPARELI J., , NI SAI J., G. LYDALL, MALONE, S. M., BURWELL, S. J., VAI DYANATHAN, U., MI U., DYANATHAN, VAI J., S. BURWELL, M., S. MALONE, AU E .P,MCHRO,T,SINY .D,D XO DI D., J. NNY, SWI T., MACPHERSON, P., E. RE, MAGUI LONG, J. C., KNOWLER, W. C., HANSON, R. L., ROBI N, N, ROBI L., R. HANSON, C., W. KNOWLER, C., J. LONG, O,K,CETN . E T . EK,D,BUIG BRUNI D., BENKE, R., ST, KEI F., , CRESTANI K., LOW, LOWETH, J. A., TSENG, K. Y. & WOLF, M. E. 2014. 2014. E. M. WOLF, & Y. K. TSENG, A., J. LOWETH, L U D D E N S ,H . ,S E E B U R G ,P .H .& K O R P I ,E .R .1 9 9 4 .Im LOH, E. W., TANG, N. L., LEE, D. T., LI U, S. I . & S & . I S. U, LI T., D. LEE, L., N. TANG, W., E. LOH, LOH, E. W., SMI TH, I . I ., MURRAY, R., MCLAUGHLI N, M N, MCLAUGHLI R., MURRAY, ., I . I TH, SMI W., E. LOH, MCBRI DE, W. J., KI MPEL, M. W., MCCLI NTI CK, J. N., D N., J. CK, NTI MCCLI W., M. MPEL, KI J., W. DE, MCBRI MCBRI DE, W. J., KI MPEL, M. W., MCCLI NTI CK, J. N., D N., J. CK, NTI MCCLI W., M. MPEL, KI J., W. DE, MCBRI CL T K .N,MBID,W . EL .L,D N DI L., R. BELL, J., W. DE, MCBRI N., J. CK, NTI MCCLI MCBRI DE, W. J., KI MPEL, M. W., MCCLI NTI CK, J. N., D N., J. CK, NTI MCCLI W., M. MPEL, KI J., W. DE, MCBRI MCBRI DE, W. J., KI MPEL, M. W., MCCLI NTI CK, J. N., D N., J. CK, NTI MCCLI W., M. MPEL, KI J., W. DE, MCBRI KI NG, S. L. 2016. 2016. L. S. NG, KI within-fam ily association and linkage analyses. analyses. linkage and dependence association alcohol ily ultiplex m within-fam in orphism polym GABRA2 adaptations in the NAc. NAc. the plasticit in synaptic adaptations Cocaine-evoked 2009. C. LUSCHER, cells of the am ygdala: a central role for alpha3 su alpha3 for role central a Neurosci, ygdala: am the of cells 45 Neurons by Extrasynaptic alpha4betadelta s. ulant im alpha4betadelta Psychost Extrasynaptic 2014. by J. J. LAMBERT, & Neurons L. S. NG, KI N., D. STEPHENS, co for responding ental cocaine. by instrum ediate m neurons electroencephalography in alcohol dependence. dependence. alcohol in single GABRA2 of study electroencephalography association A. THOMSON, Genetic ., I 2011. TH, M. SMI D., BALL, G., REYNOLDS, H., 2014. Heritability and m olecular-genetic basis of r of basis study. olecular-genetic m ion and associat Heritability 2014. BENNETT, P. H. & GOLDMAN, D. 1998. Evidence 1998. D. GOLDMAN, & H. P. BENNETT, substrate for the selective attenuation of anxiety. of attenuation selective the for & substrate H. MOHLER, H., BLUETHMANN, T., CKE, RULI ligand-binding properties of gam m a-am inobutyric aci inobutyric a-am m gam of properties ligand-binding J Med Genet B Neuropsychiatr Genet, Neuropsychiatr B Genet Med J receptor subunit genes on 5q33 with heroin heroin with 5q33 on genes subunit receptor m e ee , Genet Med J Am ncrmoo s4ad1 rm natsme-wid autosom an from 11 and 4 es osom chrom on the nucleus accum bens contributing to incubation of incubation to contributing bens accum nucleus the 76 Pt B Pt 76 cluster and alcohol dependence GAB the alcohol at and cluster variants between Association tegm ental area following repeated excessive binge-l excessive rats. (P) repeated gen preferring in following area Changes ental 2013a. A. tegm Z. RODD, & L. R. BELL, J., am ygdala following binge-like alcohol drinking by a by drinking Behav, alcohol Biochem acol binge-like Pharm Changes following ygdala 2014. am L. R. BELL, & A. Z. RODD, channels in the dorsal raphe nucleus of adol of nucleus raphe GABA-A dorsal the serotonin, in in changes channels expression Gene 2015. extended am ygdala of 5 pairs of rat lines selective lines rat of ption. pairs 5 of consum ygdala am BELL & L. extended LUMENG, J., H. EDENBERG, T., ANG, LI tegm ental area of 5 pairs of rat lines selectively selectively lines Behav, rat of Biochem acol pairs 5 Pharm of area Gen ental 2012. L. tegm R. BELL, & L. LUMENG, J., H. EDENBERG, binge-like alcohol drinking. drinking. alcohol binge-like , 810-4. 810-4. , 287-300. 287-300. 32 bioRxiv , 8611-9. 8611-9. Alcohol, 81 Psychophysiology, J Neurosci, J . . Alcohol, α , 216-21. 216-21. 4-containing GABAA receptors on on receptors GABAA 4-containing 47 Nat Neurosci, Nat , 517-29. 517-29. 117 102 47 Pharm acol Biochem Behav, Biochem acol Pharm 34 , 367-80. 367-80. in a scottish population. population. scottish a in , , 52-60. 52-60. 275-85. 275-85. , 823-38. 823-38. 51 12 144B , , 1225-45. 1225-45. AAbeta2, GABAAalpha6 and GABAAgam m a2 gene gene a2 m GABAAgam and GABAAalpha6 AAbeta2, 1036-41. 1036-41. , TADLI N, A. 2007. Association analysis of GABA GABA of analysis Association 2007. A. N, TADLI 439-43. 439-43. dependence in a Chinese m ale population. population. ale m Chinese a in dependence Adaptations in AMPA receptor transmission in in transmission receptor AMPA in Adaptations G, Z. M., LI U, Y., XUEI , X. & EDENBERG, H. J. J. H. EDENBERG, & X. , XUEI Y., U, LI M., Z. G, GABAA Receptors Modulates the Actions of of Actions the Modulates Receptors GABAA escent alcohol-preferri escent J Stud Alcohol Drugs, Alcohol Stud J RUDOLPH, U. 2000. Molecular and neuronal neuronal and Molecular 2000. U. RUDOLPH, AND, M. 2012. Tonic inhibition in principal principal in inhibition Tonic 2012. M. AND, Neurosci Lett, Neurosci I NG, Z. M., HAUSER, S. R., EDENBERG, H. H. EDENBERG, R., S. HAUSER, M., Z. NG, I in gene expression within the extended extended the within expression gene in for genetic linkage to linkage genetic for , D., LAMBERT, J. J., STEPHENS, D. N. & & N. D. STEPHENS, J., J. LAMBERT, D., , bred for high or low ethanol consum ption. ption. consum ethanol low or high for bred I NG, Z. M., EDENBERG, H. J., LI ANG, T., T., ANG, LI J., H. EDENBERG, M., Z. NG, I LLER, M. B., MCGUE, M. & I ACONO, W. G. G. W. ACONO, I & M. MCGUE, B., M. LLER, nditioned reinforcers, and its potent iation iation potent its and reinforcers, nditioned , S., MCQUI LLI N, A., GUERRI NI , I ., RAO, RAO, ., I , NI GUERRI A., N, LLI MCQUI S., , , R. L. 2013b. Gene expression within the the within expression Gene 2013b. L. R. ,

R, S. & HI LL, S. Y. 2007. The role of the the of role The 2007. Y. S. LL, HI & S. R, Science, e scan in an Am erican I ndian population. population. ndian I erican Am an in scan e I NG, Z. M., HYYTI A, P., COLOMBO, G., G., COLOMBO, P., A, HYYTI M., Z. NG, I I NG, Z. M., HYYTI A, P., COLOMBO, G., G., COLOMBO, P., A, HYYTI M., Z. NG, I , I ., BENSON, J. A., FRI TSCHY, J. M., M., J. TSCHY, FRI A., J. BENSON, ., I , p a c to fb e t aa n dg a m m av a r i a n t so n cocaine craving. craving. cocaine N, C. I ., HERD, M. B., BELELLI , D., D., , BELELLI B., M. HERD, ., I C. N, ., MCNULTY, S. & BALL, D. 2000b. 2000b. D. BALL, & S. MCNULTY, ., dolescent alcohol-preferring (P) rats. rats. (P) alcohol-preferring dolescent esting EEG activity: a genom e-wide e-wide genom a activity: EEG esting bunit-containing GABAA receptors. receptors. GABAA bunit-containing d type A receptors. receptors. A type d R. W., URBANEK, M., MOORE, E., E., MOORE, M., URBANEK, W., R. 129 ARKI TNA, J. R., SPANAGEL, R. & & R. SPANAGEL, R., J. TNA, ARKI Tonic I nhibition of Accum bal Spiny Spiny bal Accum of nhibition I Tonic y: persistence in the VTA triggers triggers VTA the in persistence y: D., MORGAN, M. Y. & GURLI NG, H. H. NG, GURLI & Y. M. MORGAN, D., fmiiswt nma o riiy orbidity: com al inim m with ilies fam ly bred for high or low ethanol ethanol low or high for bred ly o scitry, Psychiat Mol ike alcohol drinking by alcohol- by drinking alcohol ike dopam ine D2 receptor-expressing receptor-expressing D2 ine dopam receptors, neuropeptides and ion ion and neuropeptides receptors, nucleotide polym orphism s and and s orphism polym nucleotide 290 e expression within the ventral ventral the within expression e , 87-96. 87-96. 500 e expression in the ventral ventral the in expression e , 131-4. 131-4. , 162-6. 162-6. 68 ng (P) rats following following rats (P) ng erpamacology, Neuropharm alcohol dependence dependence alcohol 5 , 625-33. 625-33. , 452. 452. o hr acol, Pharm Mol mAm J

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This MORRI S, H. V., DAWSON, G. R., REYNOLDS, D. S., ATAC S., D. REYNOLDS, R., G. DAWSON, V., H. S, MORRI MORELLO, F. & PARTANEN, J. 2015. Diversity and deve and Diversity 2015. J. PARTANEN, & F. MORELLO, MOYER, J. T., WOLF, J. A. & FI NKEL, L. H. 2007. Eff 2007. H. L. NKEL, FI & A. J. WOLF, T., J. MOYER, NELSON, E. C., AGRAWAL, A., PERGADI A, M. L., LYNSKE L., M. A, PERGADI A., AGRAWAL, C., E. NELSON, MENG, Z. H. & DAR, M. S. 1994. I ntrast riat al Ro al riat ntrast I 1994. S. M. DAR, & H. Z. MENG, MENDEZ, M. A., HORDER, J., MYERS, J., COGHLA J., MYERS, J., HORDER, A., M. MENDEZ, MESSI NA, N., MARI NELLI -CASEY, P., HI LLHOUSE, LLHOUSE, HI P., -CASEY, NELLI MARI N., NA, MESSI MI HALEK, R. M., BOWERS, B. J., WEHNER, J. M., KRALI M., J. WEHNER, J., B. BOWERS, M., R. HALEK, MI MOMOSAKI , S., HOSOI , R., ABE, K. & I NOUE, O. 2010. 2010. O. NOUE, I & K. ABE, R., , HOSOI S., , MOMOSAKI MOHLER, H., FRI TSCHY, J. M. & RUDOLPH, U. RUDOLPH, & M. J. TSCHY, FRI H., MOHLER, NEWMAN, E. L., SMI TH, K. S., TAKAHASHI , A., CHU, A. CHU, A., , TAKAHASHI S., K. TH, SMI L., E. NEWMAN, MOYER, J. T., HALTERMAN, B. L., FI NKEL, L. H. & WOL & H. L. NKEL, FI L., B. HALTERMAN, T., J. MOYER, MCLEAN, P. J., FARB, D. H. & RUSSEK, S. J. 1995. J. S. RUSSEK, & H. D. FARB, J., P. MCLEAN, MELROY, W. E., STEPHENS, S. H., SAKAI , J. T., KAMEN T., J. , SAKAI H., S. STEPHENS, E., W. MELROY, MORROW, A. L., PORCU, P., BOYD, K. N. & GRANT, K. A K. GRANT, & N. K. BOYD, P., PORCU, L., A. MORROW, MEGURO, M., MI TSUYA, K., SUI , H., SHI GENAMI , K., KU K., , GENAMI SHI H., , SUI K., TSUYA, MI M., MEGURO, MCKERNAN, R. M. & WHITING, P. J. 1996. Which GABAA- MORRI S, H. V., DAWSON, G. R., REYNOLDS, D. S., ATAC S., D. REYNOLDS, R., G. DAWSON, V., H. S, MORRI MCKERNAN, R. M., ROSAHL, T. W., REYNOLDS, D. S., SU S., D. REYNOLDS, W., T. ROSAHL, M., R. MCKERNAN, N. 2008. Alpha2-containing GABA(A) receptors receptors GABA(A) cocaine. of Alpha2-containing 2008. N. neurons associated with dopam inergic nuclei. nuclei. inergic dopam with associated neurons nertv rpriso h eta titlmedi m striatal ventral the of properties integrative polym orphism s with risk of posttraum atic stress dis stress atic posttraum of a risk traum with s childhood orphism of polym A. Association GOATE, C., A. 2009. A. HEATH, P. G., MADDEN, N. N, MARTI D., R. TODD, 3731-48. 3731-48. tricodnto n titlaeoiegcmod m adenosinergic rats. in striatal and incoordination incoordination otor m em ission t om ography study. study. spectrum ography om autism t in ission em subtype alpha-5 receptor NUTT, & D. MURPHY, A., NGFORD-HUGHES, LI defects in behavioral responses to ethanol. ethanol. to subu responses delta behavioral in GABA(A)-receptor defects 2001. E. G. CS, HOMANI & binding of [ 3H] Ro15-4513 to alpha5 subtype of benzo of subtype alpha5 to brain. ouse m Ro15-4513 3H] [ of binding Childhood adverse events and m etham phetam ine use am use ine phetam etham Drugs, m and Psychoactive events adverse Childhood RUDOLPH, U. & MI CZEK, K. A. 2015. alpha2-c 2015. A. K. CZEK, MI & U. RUDOLPH, m odel of the striatal network. network. striatal the of odel m inhibition suppress asynchronous activity in a larg a in activity asynchronous suppress inhibition 234-5. 234-5. and alcohol abuse and dependence in a longitudinal longitudinal a in dependence and genetic abuse of alcohol ination and Exam BR 2014. A. S., M. K. NGER, KRAUTER, EHRI J., C. HOPFER, C., M. NGS, STALLI Pharm acol Exp Ther, Exp acol Pharm drinking behavior. st behavior. neuroactive GABAergic drinking of odulation m axis Neurosci, 1997. Evidence for uniparental, for Evidence 1997. evidence that m odern GABAA receptor gene clus gene ics, 2-al receptor GABAA Genom alpha odern an m that defines 4 e evidence osom chrom an hum to genes, using m icrocell-m ediated chrom osom e transfer e osom chrom ediated icrocell-m m using genes, brain? brain? benzodiazepine site ligands in the co t the in ediate m ligands site subtypes or recept benzodiazepine GABAA alpha3 and alpha2 anxiolytic properties of benzodiazepines ar benzodiazepines of subtype. N TI WHI properties & R. G. DAWSON, anxiolytic ., I C. W., RAGAN, K. L., MOORE, J. CASTRO, O., HOWELL, N., BROWN, GARRET A., P., MACAULAY, S, FERRI G., COOK, J., MYERS, S., FARRAR, Trends Neurosci, Trends 23 Nat Neurosci, Nat 26 Pharm acol Biochem Behav, Biochem acol Pharm , 2495-504. 2495-504. , Synapse, 580-6. 580-6. Dialogues Clin Neurosci, Clin Dialogues Suppl 5 Suppl 300 J Pharm acol Exp Ther, Exp acol Pharm J 3 64 19 , , 587-92. 587-92. 2-8. 2-8. , , 928-36. 928-36. 139-43. 139-43. , erpamacology, Neuropharm 399-409. 399-409. Front Com put Neurosci, put Com Front paternal expression of the hum an GABAA receptor su receptor GABAA an hum the of expression paternal 90 nditioned em otional response paradigm . . paradigm response otional em nditioned 15-4513 functionally antagonizes ethanol-induced ethanol-induced antagonizes functionally 15-4513 2002. A new benzodiazepine pharm acology. acology. pharm benzodiazepine new A 2002. , 9-18. 9-18. 8 Mapping of the alpha 4 subunit gene (GABRA4) (GABRA4) gene subunit 4 alpha the of Mapping N, S., STOKES, P., ERRI TZOE, D., HOWES, O., O., HOWES, D., TZOE, ERRI P., STOKES, S., N, Alcohol Clin Exp Res, Exp Clin Alcohol M., RAWSON, R., HUNTER, J. & ANG, A. 2008. 2008. A. ANG, & J. HUNTER, R., RAWSON, M., e m ediated by the GABA(A) receptor alpha1 alpha1 receptor GABA(A) the by ediated m e 271 , 463-77. 463-77. disorder: a pilot [ (11)C] Ro15-4513 positron positron Ro15-4513 (11)C] [ pilot a disorder: FEBSLett, ontaining GABA(A) receptors: a requirem ent ent requirem a receptors: GABA(A) ontaining pha 4-beta 1-gam m a 1 gene cluster: further further cluster: gene 1 a m 1-gam 4-beta pha C, J. E., VANDOREN, M. J., MORROW, A. L. L. A. MORROW, J., M. VANDOREN, E., J. C, are involved in m ediating stim ulant effects effects ulant stim ediating m in involved are S, H. M., MCQUEEN, M. B., CORLEY, R. P., P., R. CORLEY, B., M. MCQUEEN, M., H. S, eroids influences ethanol sensitivity and and sensitivity ethanol influences eroids variation in GABRA2 with conduct disorder disorder conduct with GABRA2 in variation D. 2013. The brain GABA-benzodiazepine GABA-benzodiazepine brain The 2013. D. ters are derived from an ancestral cluster. cluster. ancestral an from derived are ters , lopm ent of local inhibitory and excitatory excitatory and inhibitory local of ent lopm ects of dopam inergic m odulation on the the on odulation m inergic dopam of ects 68 524-34. 524-34. K, J. R., ROSAHL, T. W. & STEPHENS, D. D. STEPHENS, & W. T. ROSAHL, R., J. K, Y, M. T., TODOROV, A. A., WANG, J. C., C., J. WANG, A., A. TODOROV, T., M. Y, , HWA, L. S., CHEN, Y., DEBOLD, J. F., F., J. DEBOLD, Y., CHEN, S., L. HWA, , K, J. R. & STEPHENS, D. N. 2006. Both Both 2006. N. D. STEPHENS, & R. J. K, F, J. A. 2014. Lateral and feedforward feedforward and Lateral 2014. A. J. F, GOH, H., NAKAO, M. & OSHI MURA, M. M. MURA, OSHI & M. NAKAO, H., GOH, um spiny neuron. neuron. spiny um . 2006. Hypothalam ic-pituitary-adrenal ic-pituitary-adrenal Hypothalam 2006. . e, biophysically-detailed com putational putational com biophysically-detailed e, R, C., WAFFORD, K. A., ATACK, J. R., R., J. ATACK, A., K. WAFFORD, C., R, study. study. Rem arkable selectivity of the in vivo vivo in the of selectivity arkable Rem , receptor subtypes really occur in the 195-201. 195-201. 8 order in adults. adults. in order . . Hum Mol Genet, Mol Hum T, L., BRI STOW, L., MARSHALL, G., G., MARSHALL, L., STOW, BRI L., T, , ulation of ethanol-induced m otor otor m ethanol-induced of ulation 589 152. 152. nit knockout m ice have m ultiple ultiple m have ice m knockout nit diazepine receptor in the living living the in receptor diazepine G, P. J. 2000. Sedative but not not but Sedative 2000. J. P. G, Behav Genet, Behav CARLI NG, R. W., STREET, L. J., J., L. STREET, W., R. NG, CARLI OWN, S. A., HEWI TT, J. K. & & K. J. TT, HEWI A., S. OWN, M., MONTGOMERY, G. W. & & W. G. MONTGOMERY, M., , 3693-701. 3693-701. he anxiolytic properties of of properties anxiolytic he ong m en and wom en. en. wom and en m ong exposure and GABRA2 GABRA2 and exposure 25 , 1708-18. 1708-18. J Neurophysiol, J Mol Psychiatry, Mol 6 44 , 2127-33. 2127-33. , 356-67. 356-67. Eur J Eur bunit bunit 98 14 J J , ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This PARKI NSON, J. A., DALLEY, J. W., CARDI NAL, R. N., B N., R. NAL, CARDI W., J. DALLEY, A., J. NSON, PARKI PAPADEAS, S., GROBI N, A. C. & MORROW, A. L. 2 L. A. MORROW, & C. A. N, GROBI S., PAPADEAS, O L S E N ,R .W .& S P I G E L M A N ,I .2 0 1 2 .G A B A AR e c e p t o rP OLSEN, R. W. & SI EGHART, W. 2009. GABA A receptor A GABA 2009. W. EGHART, SI & W. R. OLSEN, PHI LLI PS, T. J., BELKNAP, J. K., HI TZEMANN, R. J., J., R. TZEMANN, HI K., J. BELKNAP, J., T. PS, LLI PHI OLSEN, R. W. & SI EGHART, W. 2008. I nternational Uni nternational I 2008. W. EGHART, SI & W. R. OLSEN, H L S .G IB E,H .17.Dpminergic Dopam 1973. C. H. GER, BI FI & G. A. PS, LLI PHI PETRI E, J., SAPP, D. W., TYNDALE, R. F., PARK, M. K M. PARK, F., R. TYNDALE, W., D. SAPP, J., E, PETRI PHI LLI PS, P. E. & WI GHTMAN, R. M. 2004. Extras 2004. M. R. GHTMAN, WI & E. P. PS, LLI PHI OLDS, J. & MI LNER, P. 1954. Positive reinforcem ent ent reinforcem Positive 1954. P. LNER, MI & J. OLDS, OKADA, H., MATSUSHI TA, N., KOBAYASHI , K. & KOBAYASH & K. , KOBAYASHI N., TA, MATSUSHI H., OKADA, O'DONNELL, P. & GRACE, A. A. 1995. Synaptic interac Synaptic 1995. A. A. GRACE, & P. O'DONNELL, NI E, H., REWAL, M., GI LL, T. M., RON, D. & JA & D. RON, M., T. LL, GI M., REWAL, H., E, NI O'DONNELL, P., GREENE, J., PABELLO, N., LEWI S, B. L B. S, LEWI N., PABELLO, J., GREENE, P., O'DONNELL, NUSSER, Z., SI EGHART, W. & SOMOGYI , P. 1998. 1998. P. , SOMOGYI & W. EGHART, SI Z., NUSSER, PEDEN, D. R., PETI TJEAN, C. M., HERD, M. B., DURAKO B., M. HERD, M., C. TJEAN, PETI R., D. PEDEN, PATHAK, H. R., WEI SSI NGER, F., TERUNUMA, M., CARLSO M., TERUNUMA, F., NGER, SSI WEI R., H. PATHAK, NI COLA, S. M., HOPF, F. W. & HJELMSTAD, G. O. 2004. O. G. HJELMSTAD, & W. F. HOPF, M., S. COLA, NI O'DALY, O. G., TRI CK, L., SCAI FE, J., MARSHALL, J., MARSHALL, J., FE, SCAI L., CK, TRI G., O. O'DALY, PARSI AN, A. & ZHANG, Z. H. 1999. Hum an chrom osom es es osom chrom an Hum 1999. H. Z. ZHANG, & A. AN, PARSI PARKI NSON, J. A., OLMSTEAD, M. C., BURNS, L. BURNS, C., M. OLMSTEAD, A., J. NSON, PARKI peiiePvoinapoc eaiu: mplicatio im behaviour: approach function. pa im Pavlovian depletion ine appetitive dopam bens T. accum NS, ROBBI Nucleus M., K. HALKERSTON, N., RUDARAKANCHANA, eetrmeitd3 l- paei eso m in uptake Cl(-) 36 ediated receptor-m Exp Res, Exp NOEBELS, J. L., AVOLI , M., ROGAWSKI , M. A., OLSEN, OLSEN, A., M. , (eds.) ROGAWSKI M., , AVOLI L., J. NOEBELS, alters GABA(A) receptor alpha1 and alpha4 and alpha1 receptor GABA(A) alters pharm acology. acology. pharm Behav, C. 2002. Harnessing the m ouse to unravel the geneti the unravel to ouse m the Harnessing 2002. C. pharm acology, and function. Update. Update. classificatio function. and receptors: acology, acid(A) pharm inobutyric a-am m gam Altered gabaa receptor subunit and splice variant e variant splice ethanol. and subunit intermittent receptor gabaa Altered reinforcem ent: differential effe differential ent: reinforcem Nat Neurosci, Nat eetrsbntvrat nmi m in variants subunit receptor area and other regions of rat brain. brain. rat of regions other and area 39. 39. accum bens neurons: hippocam pal gating of prefrontal of gating pal hippocam neurons: bens accum firing in the nucleus accum bens. bens. accum nucleus the in firing excitability during developm ent of tem poral lobe ep lobe poral tem of ent developm granule during dentate excitability Disrupted 2007. A. D. COULTER, m aturat ion of synaptic and extrasynaptic GA extrasynaptic and neurones. synaptic of ion J. TSCHY, FRI aturat D., m , BELELLI E., G. CS, HOMANI K., AA eetr ntencesacmbn osmedia dorsom A, S U bens Sci accum Acad Natl nucleus Proc the in receptors GABAA functional neural connectivity associated with alte with acology, associated Neuropsychopharm connectivity neural Withdrawal-associa functional 2012. T. DUKA, & N. D. STEPHENS, synaptic and extrasynaptic m em branes of cerebellar cerebellar of branes em m extrasynaptic and synaptic effect of striatal dopam ine? ine? dopam striatal of effect 703. 703. dependence: possible association with the GABRB1 ge GABRB1 the with association possible dependence: locom otor activity by D-am phetam ine. ine. phetam D-am by potent the activity and a otor locom behavior nucleus the approach of lesions of pavlovian effects in Dissociation for m idazolam -escalated aggression and social appro social and aggression -escalated idazolam m for (Berl), 232 Jasper's Basic Mechanism s of the Epilepsies. Epilepsies. the of s Mechanism Basic Jasper's 1 25 , Behav Brain Res, Brain Behav 14-26. 14-26. J Physiol, J , 4359-69. 4359-69. , 1270-5. 1270-5. 7 , erpamacology, Neuropharm 199; author reply 199. 199. reply author 199; 586 Alcohol Clin Exp Res, Exp Clin Alcohol , 108 965-87. 965-87. 137 37 Cell Tissue Res, Tissue Cell , 4459-64. 4459-64. cts of d- and l-am phetam ine. ine. phetam l-am and d- of cts dbrain dopam inergic neurons. neurons. inergic dopam dbrain , , 2267-76. 2267-76. 149-63. 149-63. Ann N Y Acad Sci, Acad Y N Ann J Com p Physiol Psychol, Physiol p Com J 56 Pharm acol Rev, acol Pharm J Neurosci, J , 141-8. 141-8. NAK, P. H. 2011. Extrasyn 2011. H. P. NAK, 25 ynaptic dopam ine and phasic neuronal activity. activity. neuronal phasic and ine dopam ynaptic 001. Chronic ethanol consum ption differentially differentially ption consum ethanol Chronic 001. 318 H., ROBBI NS, T. W. & EVERI TT, B. J. 1999. 1999. J. B. TT, EVERI & W. T. NS, ROBBI H., BUCK, K. J., CUNNI NGHAM, C. L. & CRABBE, J. J. CRABBE, & L. C. NGHAM, CUNNI J., K. BUCK, corticolim bic region bic corticolim BAA receptors in mouse thalam ic ventrobasal ventrobasal ic thalam mouse in receptors BAA , Segregation of different GABAA receptors to to receptors GABAA different of Segregation BALL, D., PHI LLI PS, M. L., WI LLI AMS, S. S., S., S. AMS, LLI WI L., M. PS, LLI PHI D., BALL, 819-28. 819-28. subunit peptide expr peptide subunit s: subtypes provide diversity of function and and function of diversity provide subtypes s: produced by electrical stim ulation of septal septal of ulation stim electrical by produced tions am ong excitatory afferents to nucleus nucleus to afferents excitatory ong am tions AMFORD, A., FEHNERT, B., LACHENAL, G., G., LACHENAL, B., FEHNERT, A., AMFORD, , GLUGI L, M. S., ROSAHL, T. W., WAFFORD, WAFFORD, W., T. ROSAHL, S., M. L, GLUGI . & GRACE, A. A. 1999. Modulation of cell cell of Modulation 1999. A. A. GRACE, & . irs both acquisition and perform ance of of ance perform and acquisition both irs iation of conditioned reinforcem ent and and ent reinforcem conditioned of iation M. & LAMBERT, J. J. 2008. Developm ental ental Developm 2008. J. J. LAMBERT, & M. ., FANSELOW, M. & OLSEN, R. W. 2001. 2001. W. R. OLSEN, & M. FANSELOW, ., and noradrenergic substrates of positive positive of substrates noradrenergic and 93-106. 93-106. cell chloride regulation enhances synaptic synaptic enhances regulation chloride cell 19 Contrast enhancem ent: a physiological physiological a ent: enhancem Contrast on of Pharm acology. LXX. Subtypes of of Subtypes LXX. acology. Pharm of on 877 red em otional regulation in alcoholism . . alcoholism in regulation otional em red ccum bens core and shell on appetitive appetitive on shell and core bens ccum ilepsy. ilepsy. 4th ed. Bethesda (MD). (MD). Bethesda ed. 4th n on the basis of subunit com position, position, com subunit of basis the on n xpression in rats treated with chronic chronic with treated rats in xpression N, G. C., HSU, F. C., MOSS, S. J. & & J. S. MOSS, C., F. HSU, C., G. N, 60 , 2401-11. 2401-11. ne. ne. cortical input. input. cortical granule cells. cells. granule l a s t i c i t yi nA l c o h o lW i t h d r a w a l . I , K. 2004. I dentification of GABAA GABAA of dentification I 2004. K. , I ns for m esoaccum bens dopam ine ine dopam bens esoaccum m for ns , cs of hum an disease. disease. an hum of cs ach in m ice. ice. m in ach 157-75. 157-75. R. W. & DELGADO-ESCUETA, A. V. V. A. DELGADO-ESCUETA, & W. R. l shell contribute to alcohol intake. intake. alcohol to contribute shell l , 243-60. 243-60. Am J Med Genet, Med J Am J Neurosci, J ted increases and decreases in in decreases and increases ted 11p15 and 4p12 and alcohol alcohol and 4p12 and 11p15 47 Science, erce , Neurochem J W. & EVERI TT, B. J. 2002. 2002. J. B. TT, EVERI & W. , 419-27. 419-27. s of rat brain. brain. rat of s 179 J Neurosci, J aptic delta-containing delta-containing aptic 27 J Neurosci, J ession and GABA(A) GABA(A) and ession Psychopharm acology acology Psychopharm , , 14012-22. 14012-22. 575-7. 575-7. 89 88 , , 7-14. 7-14. 533-8. 533-8. Genes Brain Brain Genes Alcohol Clin Clin Alcohol 18 15 , , 1693- 3622- : n: I

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This RANGASWAMY, M., PORJESZ, B., CHORLI AN, D. B., WANG, B., D. AN, CHORLI B., PORJESZ, M., RANGASWAMY, AAE,M . TOG .N,FR,M .&F FI & M. M. FORD, N., M. STRONG, J., M. RAMAKER, RAMAKER, M. J., STRONG-KAUFMAN, M. N., FORD, M. M., M. FORD, N., M. STRONG-KAUFMAN, J., M. RAMAKER, RECK, B. H., MUKHOPADHYAY, N., TSAI , H. J. & WEEKS, & J. H. , TSAI N., MUKHOPADHYAY, H., B. RECK, RANGASWAMY, M., PORJESZ, B., CHORLI AN, D. B., WANG, B., D. AN, CHORLI B., PORJESZ, M., RANGASWAMY, RAOL, Y. H., LUND, I . V., BANDYOPADHYAY, S., ZHANG, S., BANDYOPADHYAY, V., . I LUND, H., Y. RAOL, UG NO . OEH .A,M O .J,M LOVANO MI J., J. AO, MI A., J. LOWETH, A., ANTO, PURGI RADEL, M., VALLEJO, R. L., I WATA, N., ARAGON, R., L R., ARAGON, N., WATA, I L., R. VALLEJO, M., RADEL, PORJESZ, B., BEGLEI TER, H., WANG, K., ALMASY, L., C L., ALMASY, K., WANG, H., TER, BEGLEI B., PORJESZ, PLENZ, D. 2003. When inhibition goes incognito: fee incognito: goes inhibition When 2003. D. PLENZ, PORCU, P. & MORROW, A. L. 2014. Divergent neuroacti Divergent 2014. L. A. MORROW, & P. PORCU, IRE,S,SHAZR . IEETAE,A,S EGHA SI A., ESELTHALER, WI C., SCHWARZER, S., RKER, PI IEUC LGA . OAL,J,FIN,R,NLISS NELLI R., NN, FEI J., COVAULT, A., -LAGHA, ERUCCI PI PHI LLI PS, T. J., LESSOV, C. N., HARLAND, R. D. D. R. HARLAND, N., C. LESSOV, J., T. PS, LLI PHI REWAL, M., DONAHUE, R., GI LL, T. M., NI E, H., RON, RON, H., E, NI M., T. LL, GI R., DONAHUE, M., REWAL, REWAL, M., JURD, R., GI LL, T. M., HE, D. Y., RON, D RON, Y., D. HE, M., T. LL, GI R., JURD, M., REWAL, REI CH, T., EDENBERG, H. J., GOATE, A., WI LLI AMS, J. AMS, LLI WI A., GOATE, J., H. EDENBERG, T., CH, REI REYNOLDS, D. S., O'MEARA, G. F., NEWMAN, R. J., BRO J., R. NEWMAN, F., G. O'MEARA, S., D. REYNOLDS, REYNOLDS, D. S., ROSAHL, T. W., CI RONE, J., O'MEARA J., RONE, CI W., T. ROSAHL, S., D. REYNOLDS, noeatadlmie-cesehnlsl-d inist self-adm ethanol ited-access lim and operant on 64. 64. consum ption in m ice. gana ice. of m in infusions ption shell bens consum accum nucleus of Effect eednepeoyei h OAfmilies fam COGA the in phenotype dependence Resting EEG in offspring of m ale alcoholics: beta f beta alcoholics: ale m of offspring in EEG Resting BAUER, J., S. O'CONNOR, J., ROHRBAUGH, power in the EEG of alcoholics. alcoholics. of EEG the in CH REI S., power KUPERMAN, J., S. O'CONNOR, J., ROHRBAUGH, levels in hippocam pal dentate gyrus inhibits inhibits epilepsy. lobe gyrus poral dentate tem pal Enhancing hippocam in 2006. levels R. A. BROOKS-KAYAL, & J. S. RUSSEK, 51. 51. am inobutyric acid type A gene cluster. cluster. gene A al type an of acid localization inobutyric am self-a Haplotype-based cocaine 2005. acc extended-access nucleus from rat the in withdrawal late receptors GABA of expression ERP and EEG phenotypes. Li EEGphenotypes. 2002. ERPT. and CH, REI & P. J. CE, RI BAUER A., J., GOATE, ROHRBAUGH, J., S. O'CONNOR, S., KUPERMAN, 3257-72. 3257-72. neurons in striatal function. function. striatal in neurons in rat and m ouse strains: relevance for hum an studi an hum for relevance strains: ouse m and rat in receptors: im m unocytochem ical distribution distribution ical Neuroscience, unocytochem m im receptors: 1193-203. 1193-203. effects of alcohol, which are attenuated by finaste by attenuated are which alcohol, of 2005. R. effects H. KRANZLER, & L. A. MORROW, C., Genet, inbred m ice. ice. m inbred genetic associations between between associations genetic e ee , Genet Med containing GABAA receptors in the accum bens shell c shell bens accum the in alcohol. receptors GABAA containing AA eetr ntencesacmbn daemo m ediate m bens accum nucleus Neurosci, the in receptors GABAA H. 1998. Genom e-wide search for genes affecting the affecting genes for search e-wide CRO Genom K., CARR, 1998. S., H. SHEARS, W., WU, R., EL C. SCHFI NGER, TI CLONI JR., ., I J. NURNBERGER, BUCHO M., A., P. M. CONNEALLY, T, SCHUCKI V., HESSELBROCK, T., FOROUD, not show a hyperlocom otor response foll acology, response otor Neuropharm al GABA(A) hyperlocom a show 2003a. R. not G. DAWSON, & W. T. ROSAHL, J., NEWMAN, R. J., MYERS, J., SUR, C., HOWELL, O., RUTT O., HOWELL, C., SUR, J., MYERS, J., R. NEWMAN, 6 Suppl 1 Suppl 6 Addict Biol, Addict 29 81 , J Pharm acol Exp Ther, Exp acol Pharm J 543-9. 543-9. 101 , 207-15. 207-15. , S143. S143. , 815-50. 815-50. 17 44 Psychopharm acology (Berl), acology Psychopharm , 309-21. 309-21. , J Neurosci, J 190-8. 190-8. Biol Psychol, Biol Trends Neurosci, Trends ethanol tolerance and sensitization in BXD/ Ty recom Ty BXD/ in sensitization and tolerance ethanol Biol Psychiatry, Biol 26 277 , 11342-6. 11342-6. 61 Arch Gen Psychiatry, Gen Arch , 613-23. 613-23. , & MI TCHELL, S. R. 1996. Evaluat ion of potential potential of ion Evaluat 1996. R. S. TCHELL, MI & 229-48. 229-48. oo eednegn ote53 a }- a} m gam { 5q34 the to gene dependence cohol N .A 02 feto aaooeadTIP THI and ganaxolone of Effect 2012. A. D. NN, 26 owing am phetam ine or cocaine treatm ent. ent. treatm cocaine or ine phetam am owing nkage and linkage disequilibrium m apping of of apping m disequilibrium linkage and nkage epilepsy developm ent in an anim al m odel of of odel m al anim an in ent developm epilepsy 52 ONG, J. C., VI RKKUNEN, M. & GOLDMAN, D. D. GOLDMAN, & M. RKKUNEN, VI C., J. ONG, dback interaction between spiny projection projection spiny between interaction dback L. O., REI CH, T. & BEGLEI TER, H. 2004. 2004. H. TER, BEGLEI & T. CH, REI O., L. using covariates to detect linkage. linkage. detect to covariates using of 13 subunits in the adult rat brain. brain. rat adult the in subunits 13 of . & JANAK, P. H. 2009. Alpha4-containing Alpha4-containing 2009. H. P. JANAK, & . , ERY, M., HERNANDEZ-AVI LA, C., ONCKEN, ONCKEN, C., LA, HERNANDEZ-AVI M., ERY, ve steroid responses to stress and ethanol ethanol and stress to responses steroid ve D. & JANAK, P. H. 2012. Alpha4 subunit- Alpha4 2012. H. P. JANAK, & D. 436-43. 436-43. MI DGE, F. A., ATACK, J. R., WHI TI NG, P. P. NG, TI WHI R., J. ATACK, A., F. DGE, MI GABRA2 alleles m oderate the subjective subjective the oderate m alleles GABRA2 , 232 requencies. requencies. T., RI CE, J. P., VAN EERDEWEGH, P., P., EERDEWEGH, VAN P., J. CE, RI T., 831-42. 831-42. VI C, M. & WOLF, M. E. 2016. Surface Surface 2016. E. M. WOLF, & M. C, VI dm inistration. inistration. dm G., ROBERTS, D. S., WOLFE, J. H., H., J. WOLFE, S., D. ROBERTS, G., PHI LLI PS, T. J. & FI NN, D. A. 2015. 2015. A. D. NN, FI & J. T. PS, LLI PHI RT, W. & SPERK, G. 2000. GABA(A) GABA(A) 2000. G. SPERK, & W. RT, ration. ration. ride. ride. um bens is increased in early but not not but early in increased is bens um es. es. ontribute to the reinforcing effects of of effects reinforcing the to ontribute , K., JONES, K. A., KUPERMAN, S., S., KUPERMAN, A., K. JONES, K., HORLI AN, D. B., STI MUS, A. T., T., A. MUS, STI B., D. AN, HORLI 1415-26. 1415-26. K., JONES, K. A., BAUER, L. O., O., L. BAUER, A., K. JONES, K., risk for alcohol dependence. dependence. alcohol for risk , G. F., HAYTHORNTHWAI TE, A., A., TE, HAYTHORNTHWAI F., G. , D. E. 2005. Analysis of alcohol alcohol of Analysis 2005. E. D. GABA(A) receptor alpha 1 subunit subunit 1 alpha receptor GABA(A) xolone or gaboxadol on ethanol ethanol on gaboxadol or xolone ER, A. R., ATACK, J., MACAULAY, MACAULAY, J., ATACK, R., A. ER, SE, C., WI LLI G, C. & BEGLEI TER, TER, BEGLEI & C. G, LLI WI C., SE, Psychopharm acology (Berl), acology Psychopharm pha 1 subunit knock-out m ice do do ice m knock-out subunit 1 pha , T. & BEGLEI TER, H. 2002. Beta Beta 2002. H. TER, BEGLEI & T. , erpyhpamacology, Neuropsychopharm 62 LZ, K., PORJESZ, B., LI , T. K., K., T. , LI B., PORJESZ, K., LZ, erpamacology, Neuropharm derate intake of alcohol. alcohol. of intake derate I nt J Psychophysiol, J nt I D, J. A., CROWE, R. R., R., R. CROWE, A., J. D, , L. O., EDENBERG, H. J., J., H. EDENBERG, O., L. , , 47-55. 47-55. Brain Res Brain . . 63 51 , binant binant , 555- 231 239- Am J Am 30 BMC BMC J , ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This SANNA, E., TALANI , G., BUSONERO, F., PI SU, M. G. M. SU, PI F., BUSONERO, G., , TALANI E., SANNA, SANDER, T., SAMOCHOWI EC, J., LADEHOFF, M., SMOLKA, SMOLKA, M., LADEHOFF, J., EC, SAMOCHOWI T., SANDER, RUSSEK, S. J. & FARB, D. H. 1994. Mapping Mapping 1994. H. D. FARB, & J. S. RUSSEK, S A L A M O N E ,J .D .& C O R R E A ,M .2 0 1 2 .T h em y s t e r i o u sm RUDOLPH, U. & KNOFLACH, F. 2011. Beyond classical b classical Beyond 2011. F. KNOFLACH, & U. RUDOLPH, RUEDI -BETTSCHEN, D., ROWLETT, J. K., RALLAPALLI , S. , RALLAPALLI K., J. ROWLETT, D., -BETTSCHEN, RUEDI SABA, L. M., BENNETT, B., HOFFMAN, P. L., BARCOM L., P. HOFFMAN, B., BENNETT, M., L. SABA, RUDOLPH, U., CRESTANI , F., BENKE, D., BRUNI G, I ., B ., I G, BRUNI D., BENKE, F., , CRESTANI U., RUDOLPH, ROWLETT, J. K., PLATT, D. M., LELAS, S., ATAC S., LELAS, M., D. PLATT, K., J. ROWLETT, ROH, S., MATSUSHI TA, S., HARA, S., MAESATO, H., MAT H., MAESATO, S., HARA, S., TA, MATSUSHI S., ROH, CWRE,C,BREHIM . IRE,S,W ESELTH WI S., RKER, PI U., M, BERRESHEI C., SCHWARZER, ROBI NSON, T. E. & BERRI DGE, K. C. 1993. The neural neural The 1993. C. K. DGE, BERRI & E. T. NSON, ROBI RI SI NGER, F. O. & CUNNI NGHAM, C. L. 1998. Etha 1998. L. C. NGHAM, CUNNI & O. F. NGER, SI RI REYNOLDS, L. M., ENGI N, E., TANTI LLO, G., LAU, H. M H. LAU, G., LLO, TANTI E., N, ENGI M., L. REYNOLDS, SCHULTZ,DAYAN,W., P.MONTAGUE,& P.ne AR. 1997. SCHULTZ, W. 2016. Dopam ine reward prediction reward ine Dopam 2016. W. SCHULTZ, SANTHAKUMAR, V., JONES, R. T. & MODY, I . 2010. . I MODY, & T. R. JONES, V., SANTHAKUMAR, SCHARFMAN, H. E. & BROOKS-KAYAL, A. R. 2014. I s pla s I 2014. R. A. BROOKS-KAYAL, & E. H. SCHARFMAN, SCHUMANN, G., LOTH, E., BANASCHEWSKI , T., BARBOT, A BARBOT, T., , BANASCHEWSKI E., LOTH, G., SCHUMANN, R O B B I N S ,T .W .& E V E R I T T ,B .J .2 0 0 7 .A r o l ef o rm e the gene encoding the GABAB receptor and alcohol de alcohol and receptor GABAB the encoding Associatio gene the 1999. G. L. DT, SCHMI & H. ROMMELSPACHER, 73. 73. dopam ine. ine. dopam of GABAA receptor subtypes. subtypes. receptor GABAA of M. 2013. Modulation of alpha5 subunit-containing GA onkeys. subunit-containing m alpha5 rhesus of by Modulation 2013. M. m icrodissected hum an chrom osom e 5q34-q35 defines a a . defines isoform 5q34-q35 e receptor GABAA osom chrom abundant an hum icrodissected m brain GABAergic transm ission. drinkin ission. alcohol of transm analysis GABAergic brain genetic s system A 2011. gam m a-am inobutyric acid(A inobutyric Benz a-am m gam 1999. H. MOHLER, & H. BLUETHMANN, R., benzodiazepine-like drugs in prim ates. ates. prim in abuse-rel drugs anxiolytic, the ediate benzodiazepine-like m subtypes receptor subjective responses to alcohol. alcohol. to responses subjective R A M C H A N D A N I ,V .A . ,L I ,T .K .& H I G U C H I ,S .2 0 1 1 .R 526-49. 526-49. in the basal ganglia and associated lim bic brain ar brain bic lim associated ga and major ganglia the basal of the in Distribution 2001. G. SPERK, m ediated by distinct GABA(A) receptor isoform s. s. isoform receptor GABA(A) distinct 2003b by A. K. ediated WAFFORD, m & J. D. P. , NG, BELELLI TI H., WHI P. R., HUTSON, MCKERNAN, L., K. NGHAM, HADI J., A. 40. 40. induced enhancem ent of brain-stim ulation reward. reward. ulation brain-stim of GA ent of roles enhancem induced Differential 2012. U. RUDOLPH, & sensitization theory of addiction. addiction. of theory sensitization to epileptogenesis? epileptogenesis? to Brain steroidogenesis m ediates ethanol m odulation o odulation m ethanol pus. ediates m hippocam steroidogenesis Brain enocmetrltdbhvori omnorm in ry, behaviour Psychiat ent-related 2010. . I UM, reinforcem CONSORTI & M. STRUVE, SPANAGE A., M., STROHLE, SMOLKA, N., L., REED, L., M., J. ETSCHEL, NOT, RI MARTI W., K., T. MANN, C., GARAV K, J., MALLI NAT, M., GALLI LATHROP, H., FLOR, W., J. DALLEY, J., P. Science, com m entary on Berridge (2006). (2006). Berridge on entary m com recom binant inbred m ice. ice. m inbred binant recom Rev Neurosci, Rev effects of striatal tonic GABAA currents. currents. GABAA tonic striatal of effects 275 15 Neuron, , 1593-9. 1593-9. 17 , J Neurosci, J 1128-39. 1128-39. , 183-95. 183-95. 76 Adv Exp Med Biol, Med Exp Adv Alcohol Clin Exp Res, Exp Clin Alcohol , 470-85. 470-85. 24 Alcohol Clin Exp Res, Exp Clin Alcohol ) receptor subtypes. subtypes. receptor ) , 6521-30. 6521-30. Nat Rev Drug Discov, Drug Rev Nat erpamacology, Neuropharm Alcohol Clin Exp Res, Exp Clin Alcohol Brain Res Brain Res Rev, Res Brain Res Brain Psychopharm acology (Berl), acology Psychopharm eo ics, Genom 813 Proc Natl Acad Sci U S A, S U Sci Acad Natl Proc Neuroscience, K, J. R. & DAWSON, G. R. 2005. Different GABAA GABAA Different 2005. R. G. DAWSON, & R. J. K, -error signalling: a two-com ponent response. response. ponent two-com a signalling: -error 37 , 133-50. 133-50. al brain function and psychopathology. psychopathology. and function brain al Developm ental regulation and neuroprotective neuroprotective and regulation ental Developm , PURDY, R. H., SERRA, H., R. PURDY, , nol-induced conditioned taste aversion in BXD BXD in aversion taste conditioned nol-induced , of the beta 2 subunit gene (GABRB2) to to (GABRB2) gene subunit 2 beta the of B, K., I SHI I , T., KECHRI S, K. & TABAKOFF, B. B. TABAKOFF, & K. S, KECHRI T., , I SHI I K., B, 624-34. 624-34. 23 m m a-am inobutyric acid(A) receptor subunits subunits receptor acid(A) inobutyric a-am m m BA(A) receptor subtypes in benzodiazepine- in subtypes receptor BA(A) 22 ., MUSCHAMP, J. W., CARLEZON, W. A., JR. JR. A., W. CARLEZON, W., J. MUSCHAMP, ., enzodiazepines: novel therapeutic potential potential therapeutic novel enzodiazepines: ENSON, J. A., FRI TSCHY, J. M., MARTI N, J. J. N, MARTI M., J. TSCHY, FRI A., J. ENSON, Nature, , J Neurosci, J sticity of GABAergic m echanism s relevant relevant s echanism m GABAergic of sticity , CLAYTON, T., COOK, J. M. & PLATT, D. D. PLATT, & M. J. COOK, T., CLAYTON, , 528-33. 528-33. eas of the adult rat. rat. adult the of eas , odiazepine actions m ediated by specific specific by ediated m actions odiazepine 10 ural substratepredictionuralof reward. and 1234-44. 1234-44. 60 ALER, A., FUCHS, K., SI EGHART, W. & & W. EGHART, SI K., FUCHS, A., ALER, g by m ice, rats and m en: influence of of influence en: m and rats ice, m by g ., BARKER, G., BUCHEL, C., CONROD, CONROD, C., BUCHEL, G., BARKER, ., erpyhpamacology, Neuropsychopharm SUI , T., SUZUKI , G., MI YAKAWA, T., T., YAKAWA, MI G., , SUZUKI T., , SUI basis of drug craving: an incentive- an craving: drug of basis 35 s e n c e p h a l i cd o p a m i n ei na c t i v a t i o n : BAA receptors alters alcohol drinking drinking alcohol alters receptors BAA , 167 685-97. 685-97. , o t i v a t i o n a lf u n c t i o n so fm e s o l i m b i c PAUS, T., POLI NE, J. B., ROBBI NS, NS, ROBBI B., J. NE, POLI T., PAUS, 1269-80. 1269-80. AN, H., HEI NZ, A., I TTERMAN, B., B., TTERMAN, I A., NZ, HEI H., AN, , LAMBERT, J. J., DAWSON, G. R., R., G. DAWSON, J., J. LAMBERT, , pendence. pendence. f GABAA receptor activit y in rat rat in y activit receptor GABAA f , 401 L, R., SPEI SER, C., STEPHENS, D. D. STEPHENS, C., SER, SPEI R., L, 400-7. 400-7. 18 , n analysis of exonic variants of of variants exonic of analysis n ated, and m otor effects of of effects otor m and ated, 644-55. 644-55. M., PETERS, C., RI ESS, O., O., ESS, RI C., PETERS, M., 23 o l eo fG A B R A 2i nm o d e r a t i n g , , 191 796-800. 796-800. 247-91. 247-91. gene cluster for the m ost ost m the for cluster gene , . Sedation and anesthesia anesthesia and Sedation . 8608-17. 8608-17. 102 , 433-7. 433-7. Psychiatr Genet, Psychiatr M. & BI GGI O, G. 2004. 2004. G. O, GGI BI & M. , h AE td:study: MAGEN I The 915-20. 915-20. J Com p Neurol, p Com J 37 , 9 2531- 433 , 69- Nat Nat Mol Mol ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This STEPHENS, D. N. & DUKA, T. 2008. Review. Co Review. 2008. T. DUKA, & N. D. STEPHENS, TPES .N,BON . UA .&R PLEYRI & T. DUKA, G., BROWN, N., D. STEPHENS, OK,M,PES,U . ESLRC,V,Z ZI V., HESSELBROCK, W., U. PREUSS, M., SOYKA, STEIN,PAULUS,B.,M. P.GELERNTER,M.& G J. 2006. STANKI EWI CZ, A. M., GOSCI K, J., DYR, W., JUSZCZAK, JUSZCZAK, W., DYR, J., K, GOSCI M., A. CZ, EWI STANKI SONG, J., KOLLER, D. L., FOROUD, T., CARR, K., ZHAO K., CARR, T., FOROUD, L., D. KOLLER, J., SONG, SONG, I ., SAVTCHENKO, L. & SEMYANOV, A. 2011. Tonic 2011. A. SEMYANOV, & L. SAVTCHENKO, ., I SONG, SOMMER, B., POUSTKA, A., SPURR, N. K. & SEEBURG, P. SEEBURG, & K. N. SPURR, A., POUSTKA, B., SOMMER, SMI TH, K. W., GI ERSKI , F., ANDRE, J., DOWELL, N. G. N. DOWELL, J., ANDRE, F., , ERSKI GI W., K. TH, SMI SMI TH, K. S., ENGI N, E., MELONI , E. G. & RUDOLPH, U RUDOLPH, & G. E. , MELONI E., N, ENGI S., K. TH, SMI SI LBERBERG, G. & BOLAM, J. P. 2015. Local and affer and Local 2015. P. J. BOLAM, & G. LBERBERG, SI SI LVERI , M. M., SNEI DER, J. T., CROWLEY, D. J., COV J., D. CROWLEY, T., J. DER, SNEI M., M. , LVERI SI SHI NDAY, N. M., SAWYER, E. K., FI SCHER, B. D., PLAT D., B. SCHER, FI K., E. SAWYER, M., N. NDAY, SHI STEPHENS, D. N., PI STOVCAKOVA, J., WORTHI NG, L. NG, WORTHI J., STOVCAKOVA, PI N., D. STEPHENS, U,C,WFOD .A,RYOD,D . AINGHAM HADI S., D. REYNOLDS, A., K. WAFFORD, C., SUR, STRAUB, C. J., CARLEZON, W. A., JR. & RUDOLPH, & JR. A., W. CARLEZON, J., C. STRAUB, TPES .N,DK,T,COBG .S,CNINGH CUNNI S., H. CROMBAG, T., DUKA, N., D. STEPHENS, TA,D . RAE,G . EKV ,M . V G SVI N., M. C, PERKOVI N., G. ERJAVEC, S., D. STRAC, SEN, S., VI LLAFUERTE, S., NESSE, R., STOLTENBERG, S STOLTENBERG, R., NESSE, S., LLAFUERTE, VI S., SEN, drinking: role of am ygdala and prefrontal cortex. cortex. prefrontal and ygdala am of role drinking: enhanced seizure sensitivity in rats given repeated given rats in Neurosci, J Eur sensitivity seizure enhanced of the hum an am ygdala and and ygdala am an hum the of of Warsaw alcohol-preferring and non-preferring rat non-preferring cortex and edial m alcohol-preferring prefrontal of Warsaw of analysis ic candidate Novel transcriptom 2015. R. , STEFANSKI & M. ECZOREK, WI 38. 38. Association of GABA(A) receptors and alcohol depend alcohol and printing. receptors im GABA(A) of L., T. Association TH, SMI B., PORJESZ, H., TER, BEGLEI receptor subunit gene (GABRA2) polym orphism s and ri and s orphism polym Res, r (GABRA2) Psychiat gene subunit receptor 561-8. 561-8. conductance in hippocampal interneurons. interneurons. hippocampal in conductance delta-subunit gene: structure and as and structure gene: delta-subunit young social drinkers with binge drinking pattern. pattern. br drinking whole binge in with integrity drinkers atter social m young white Altered 2015. T. and reduction of conditioned fear are m ediated by d by ediated m are fear ice. m conditioned of reduction and m icrocircuitry. icrocircuitry. m soitoswt mpliiyadrsos nii i inhibit response and pulsivity in im a-am with m gam lobe associations Frontal 2013. E. J. JENSEN, 38 com pounds lacking intrinsic efficacy at alpha1 subu cocaine- not alpha1 at but - efficacy idazolam m in intrinsic lacking pounds ROWLE & com S. D. REYNOLDS, R., G. DAWSON, 18. 18. variants are associated with neuroticism . . neuroticism with associated are Serotoni variants 2004. M. STER, BURMEI & A. WEDER, deletion, and a selective inverse agonist. agonist. inverse etha selective a in and receptors deletion, alpha5-containing GABAA of m ajor GABA(A) receptor subtype in the brain is not not is brain the in subtype RO receptor & J. P. GABA(A) NG, TI ajor WHI m M., R. MCKERNAN, R., R., NEWMAN, G. O., DAWSON, HOWELL, G., O'MEARA, N., NSON, COLLI 119-25. 119-25. 3169-79. 3169-79. brain stim ulation reward in C57BL/ 6J m ice. ice. m 6J C57BL/ in reward ulation stim brain hum an and anim al phenotypes. eas phenotypes. m al of anim issues and an hum sensitivity: Reward 2010. dependence-related aggressive behavior. behavior. subunit aggressive alpha2 receptor GABAA dependence-related of Association 2015. , 1006-14. 1006-14. erpamacology, Neuropharm Am J Med Genet B Neuropsychiatr Genet, Neuropsychiatr B Genet Med J Am 42 14 Curr Opin Neurobiol, Opin Curr , 184-91. 184-91. , 2023-31. 2023-31. 63 insula to fearful faces. faces. fearful to insula , 250-8. 250-8. Addict Biol, Addict experienced rhesus m onkeys. onkeys. m rhesus experienced 33 signm ent to hum an chrom osom e 1. 1. e osom chrom an hum to ent signm , 182-7. 182-7. u hr acol, Pharm J Eur Biol Psychiatry, Biol Prog Neuropsychopharm acol Biol Psychiatry, Biol acol Neuropsychopharm Prog LL, P., KOLLER, G. & BONDY, B. 2008. GABA-A2 GABA-A2 2008. B. BONDY, & G. KOLLER, P., LL, a o un, m Com Nat 15 gnitive and em otional consequences of binge binge of consequences otional em and gnitive Behav Brain Res, Brain Behav urem ent, and achieving consilience between between consilience achieving and ent, urem , T. L. 2001. I m paired fear conditioning but but conditioning fear paired m I 2001. L. T. , U. 2010. Diazepam and cocaine pot ent iate iate ent pot cocaine and Diazepam 2010. U. SCHUCKIT, M. A. & EDENBERG, H. J. 2003. , ATACK, J. R. & DAWSON, G. R. 2005. Role Role 2005. R. G. DAWSON, & R. J. ATACK, , , 145-68. 145-68. n transporter and GABAA alpha 6 receptor receptor 6 alpha GABAA and transporter n , CERCI GNANI , M., NAASSI LA, M. & DUKA, DUKA, & M. LA, NAASSI M., , GNANI CERCI , nol reward: the effects of targeted gene gene targeted of effects the reward: nol ELL, M. J., ACHARYA, D., ROSSO, I . M. & & M. . I ROSSO, D., ACHARYA, J., M. ELL, ABRA2geneticresponsevariationthe and . 2012. Benzodiazepine-induced anxiolysis anxiolysis Benzodiazepine-induced 2012. . G. R., RYGLEWI CZ, D., SWI ERGI EL, A. H., H., A. EL, ERGI SWI D., CZ, RYGLEWI R., G. btrcai eesdrn dlsec:adolescence: during levels acid obutyric excitation or inhibition is set by GABA(A) GABA(A) by set is inhibition or excitation on. on. LI N, K. N., BOROVECKI , F. & PI VAC, N. N. VAC, PI & F. , BOROVECKI N., K. N, LI TT, J. K. 2013. Reinforcing effects of of effects Reinforcing 2013. K. J. TT, Addict Biol Addict Philos Trans R Soc Lond B Biol Sci, Biol B Lond Soc R Trans Philos T, D. M., LI CATA, S. C., ATACK, J. R., R., J. ATACK, C., S. CATA, LI M., D. T, , J., RI CE, J., NURNBERGER, J. I ., JR., JR., ., I J. NURNBERGER, J., CE, RI J., , ain and segm ents of corpus callosum , in in , callosum corpus of ents segm and ain nit-containing GABAA receptor subtypes subtypes receptor GABAA nit-containing , hippocam pus and nucleus accum bens bens accum nucleus and pus hippocam , experience of withdrawal from alcohol. alcohol. from withdrawal of experience Biological Psychiatry, Biological H. 1990. The m urine GABAA receptor receptor GABAA urine m The 1990. H. AM, C. L., HEI LI G, M. & CRABBE, J. C. C. J. CRABBE, & M. G, LI HEI L., C. AM, ent synaptic pathways in the striatal striatal the in pathways synaptic ent , K. L., BROMI DGE, F., MACAULAY, A., A., MACAULAY, F., DGE, BROMI L., K. , s. s. . F., HOPCI AN, J., GLEI BERMAN, L., L., BERMAN, GLEI J., AN, HOPCI F., . 117B Biol Psychiatry, Biol lethal in m ice. ice. m in lethal Pharm acol Biochem Behav, Biochem acol Pharm istinct GABAA receptor subtypes in in subtypes receptor GABAA istinct 2 55 ence and the effects of genetic genetic of effects the and ence 526 , , 376. 376. 39-45. 39-45. sk for alcohol dependence. dependence. alcohol for sk SAHL, T. W. 2001. Loss of the the of Loss 2001. W. T. SAHL, , gene (GABRA2) with alcohol alcohol with (GABRA2) gene 244-9. 244-9. . . 206 , MYERS, J., ATACK, J. R., R., J. ATACK, J., MYERS, 240-50. 240-50. erpyhpamacology, Neuropsychopharm gnsfrachls -- alcoholism for genes , 17-20. 17-20. 74 J Neurosci, J , 59 296-304. 296-304. DNA Cell Biol, Cell DNA , 179S-179S. 179S-179S. 21 139 , 3409- 363 , 27- 63 9 J , , ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This TRUCCO, E. M., VI LLAFUERTE, S., HEI TZEG, M. M., BUR M., M. TZEG, HEI S., LLAFUERTE, VI M., E. TRUCCO, USAL .J,ORCO,D . EN .&W CKEN WI & A. KEAN, E., D. OORSCHOT, J., M. TUNSTALL, TEPPER, J. M., WI LSON, C. J. & & J. C. LSON, WI M., TEPPER, J. TRACY, M. E., BANKS, M. L. & SHELTON, K. L. 2016. N 2016. L. K. SHELTON, & L. M. BANKS, E., M. TRACY, RCO .M,H K,B . ILAURE . IGG, NI S., LLAFUERTE, VI M., B. CKS, HI M., E. TRUCCO, TRUCCO, E. M., VI LLAFUERTE, S., HEI TZEG, M. M., BUR M., M. TZEG, HEI S., LLAFUERTE, VI M., E. TRUCCO, TEPPER, J. M., ABERCROMBI E, E. D. & BOLAM, & D. E. E, ABERCROMBI M., TEPPER, J. ALR .M,CSOGA,A,GOH,A,VYS ER VAYSSI A., GHOGHA, A., CASTONGUAY, M., A. TAYLOR, TAN, K. R., BROWN, M., LABOUEBE, G., YVON, C., CRET C., YVON, G., LABOUEBE, M., BROWN, R., K. TAN, ACUK .A,LN,S . OD .M,HSIMOT HASHI M., M. FORD, L., S. LONG, A., M. TANCHUCK, TABAKOFF, B., SABA, L., PRI NTZ, M., FLODMAN, FLODMAN, M., NTZ, PRI L., SABA, B., TABAKOFF, VARGAS-PEREZ, H., TI NG, A. K. R., WALTON, C. H., HA H., C. WALTON, R., K. A. NG, TI H., VARGAS-PEREZ, VASHCHI NKI NA, E., PANHELAI NEN, A., VEKOVI SCHEVA, O. SCHEVA, VEKOVI A., NEN, PANHELAI E., NA, NKI VASHCHI VI CI NI , S., FERGUSON, C., PRYBYLOWSKI , K., KRALI C, C, KRALI K., , PRYBYLOWSKI C., FERGUSON, S., , NI CI VI SWANSON, A. M., ALLEN, A. G., SHAPI RO, L. P. & GOUR & P. L. RO, SHAPI G., A. ALLEN, M., A. SWANSON, UHART, M., WEERTS, E. M., MCCAUL, M. E., GUO, X., Y X., GUO, E., M. MCCAUL, M., E. WEERTS, M., UHART, UUI,T,AE . AAUH . AA . OI, HORI A., BABA, M., , YAMAGUCHI S., ABE, T., , SUZUKI SURMEI ER, D. J., DI NG, J., DAY, M., WANG, Z. & SHEN & Z. WANG, M., DAY, J., NG, DI J., D. ER, SURMEI TZANOULI NOU, S., RI CCI O, O., DE BOER, M. W. W. M. BOER, DE O., O, CCI RI S., NOU, TZANOULI Susceptibility effects of GABA receptor subunit alp subunit receptor GABA of effects Susceptibility m onitoring on externalizing behavior trajecto behavior allele. inor m externalizing on onitoring m between spiny projection neurons in the rat striatu rat the in neurons projection spiny between eetr niisfcltto fbansi ul stim brain of ice. m facilitation inhibits receptors breaking m ediates the developm ental asso ental abuse. developm substance the ediates m breaking 2016a. Tem peram ent and Externalizing Behavior as Me as Behavior Use. Externalizing Substance and Adolescent ent peram Tem 2016a. Res, GABAergic spiny neurons. neurons. spiny GABAergic 41 Tegm ental Area During Withdrawal from Chronic Morph Chronic from Withdrawal During Regulation Area une m ental Tegm Neuroim C., 2016. M. M. OLMSTEAD, C. LL, P., CAHI TT, LEVI J., WU, S., , MEHRABANI LUSCHER, C. 2010. Neural bases for addictive proper addictive for bases Neural 2010. C. LUSCHER, 769-74. 769-74. WI REN, K. M. & FI NN, D. A. 2009. Selected Selected 2009. A. D. NN, FI & M. K. REN, WI dependence and withdrawal on allopregnanolone level expression. allopregnanolone and on activity withdrawal and dependence 2009. Genetical genom ic determ inants of alcohol con alcohol of inants determ ic Biol, genom Genetical W. STATE, 2009. L., P. HOFFMAN, K B., GRAVE, GRANT, CONI J., M., ER, SAUNDERS, DONGI L., HUBNER LEGAULT, L., J., R. BELL, ON, MANGI K., S, KECHRI N., H. CHARDSON, RI plasticity in the orbitofrontal cortex regu acology, cortex Neuropsychopharm orbitofrontal the in plasticity 357-69. 357-69. tegm ental area BDNF induces an opiate-dependent-lik an induces BDNF area C. S. STEFFENSEN, ental W., tegm D. SON, ALLI R., M. NO, BUFALI 324 persistent changes in ventral tegm ental area ental tegm baboons. or ice ventral m in changes agon site GABA persistent 2012. R. E. , KORPI & A. N. inhibitory synaptic currents in cerebellar neurons. cerebellar in prev currents deletion synaptic subunit alpha1 inhibitory receptor GABA(A) 2001. Neurosci, of cocaine adm inistration on receptor binding and s and plexes. com binding receptor receptor on benzodiazepine inistration adm cocaine of m odulation of striatal glutam atergic signaling in s in signaling atergic glutam striatal of odulation m G. S. 2013. GABRA2 m arkers m oderate the subjective subjective the oderate m arkers m GABRA2 2013. S. G. and inhibition in the am ygdala. ygdala. am the altered in with inhibition associated and are changes behavioral , 949-59. 949-59. , 160 7 1732-4. 1732-4. Psychopharm acology (Berl), acology Psychopharm , 70. 70. , 30 3-7. 3-7. , Dev Psychopathol, Dev 228-35. 228-35. J Neurosci, J J Child Psychol Psychiatry, Psychol Child J Alcohol Clin Exp Res, Exp Clin Alcohol KOOS, T. 2008. Feedforward and feedback inhibition inhibition feedback and Feedforward 2008. T. KOOS, Brain Res Rev, Res Brain J Abnorm Psychol Abnorm J 40 32 , 28 1027-36. 1027-36. Transl Psychiatry, Transl , 5310-20. 5310-20. 233 , 15-26. 15-26. Synapse, , 715-25. 715-25. J. P. 2007. Basal ganglia m acrocircuits. acrocircuits. m ganglia Basal 2007. P. J. 58 P., HODGKI NSON, C., GOLDMAN, D., KOOB, G., G., KOOB, D., GOLDMAN, C., NSON, HODGKI P., & SANDI , C. 2014. Peripubertal stress-induced stress-induced Peripubertal 2014. C. , SANDI & 55 , 272-81. 272-81. . . to eadb rg fauei 5B6 J C57BL6/ in abuse of drugs by reward ation 33 38 dopam ine neurons but is not rewarding in in rewarding not is but neurons ine dopam lates context-dependent action selection. selection. action context-dependent lates ciation between GABRA2 and adolescent adolescent and GABRA2 between ciation ries: Risk and protection conveyed by the the by conveyed protection and Risk ries: , ist gaboxadol induces addiction-predicting addiction-predicting induces gaboxadol ist of GABAergic Neurons Within the Ventral Ventral the Within Neurons GABAergic of 1372-9. 1372-9. T., SHI RAI SHI , H. & I TO, T. 2000. Effects Effects 2000. T. TO, I & H. , SHI RAI SHI T., , AN, X., KRANZLER, H. R., LI , N. & WAND, WAND, & N. , LI R., H. KRANZLER, X., AN, expression of genes involved in excitation excitation in involved genes of expression , W. 2007. D1 and D2 dopam ine-receptor ine-receptor dopam D2 and D1 2007. W. , J. T., BURMEI STER, M. & ZUCKER, R. A. A. R. ZUCKER, & M. STER, BURMEI T., J. MEI STER, M. & ZUCKER, R. A. 2014. Rule Rule 2014. A. R. ZUCKER, & M. STER, MEI 2077-87. 2077-87. , line difference in the effects of ethanol ethanol of effects the in difference line 4 ON, C., FRI TSCHY, J. M., RUDOLPH, U. & & U. RUDOLPH, M., J. TSCHY, FRI C., ON,

198-215. 198-215. LEY, S. L. 2015. GABAAalpha1-m ediated ediated GABAAalpha1-m 2015. L. S. LEY, J Neurosci, J J., MORROW, A. L. & HOMANI CS, G. E. E. G. CS, HOMANI & L. A. MORROW, J., m . . m egative allosteric m odulation of GABAA GABAA of odulation m allosteric egative NSEN, D. M., RAZAVI , R., CLARKE, L., L., CLARKE, R., , RAZAVI M., D. NSEN, MEI STER, M. & ZUCKER, R. A. 2016b. 2016b. A. R. ZUCKER, & M. STER, MEI , e410. e410. triatal m edium spiny neurons. neurons. spiny edium m triatal O, J., CRABBE, J. C., ROSELLI , C. E., E., C. , ROSELLI C., J. CRABBE, J., O, Y., AI TTA-AHO, T., EBERT, B., ATOR, ATOR, B., EBERT, T., TTA-AHO, AI Y., ha-2 (GABRA2) variants and parental parental and variants (GABRA2) ha-2 S, J. R. 2002. I nhibitory interactions interactions nhibitory I 2002. R. J. S, ties of benzodiazepines. benzodiazepines. of ties J Neurophysiol, J e reward state in naive rats. rats. naive in state reward e sum ption in rats and hum ans. ans. hum and rats in ption sum E, P., PRADHAN, A. A., XUE, L., L., XUE, A., A. PRADHAN, P., E, & VAN DER KOOY, D. 2009. Ventral Ventral 2009. D. KOOY, DER VAN & DE KONI NCK, Y., EVANS, C. J. & & J. C. EVANS, Y., NCK, KONI DE effects of alcohol. alcohol. of effects I . S. O. & TRAI T MARKERS OF, A. A. OF, MARKERS T TRAI & O. S. . I s and 5alpha-reductase enzym e e enzym 5alpha-reductase and s , N., HEI NI G, M., PRAVENEC, M., M., PRAVENEC, M., G, NI HEI N., , ents developm ental changes of of changes ental developm ents ine. ine. bnt N fGB(A)- GABA( of RNA m ubunits 21 diators of Genetic Risk on on Risk Genetic of diators erpyhpamacology, Neuropsychopharm , . M., WHI TFI ELD, J. B., B., J. ELD, TFI WHI M., . 3009-16. 3009-16. 88 , 1263-9. 1263-9. Addict Biol, Addict in neostriatal neostriatal in Nature, Prog Brain Brain Prog Science, Trends Trends 463 BMC 18 , ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This WI ELAND, H. A. & LUDDENS, H. 1994. Four am ino ino am Four 1994. H. LUDDENS, & A. H. ELAND, WI WI LCOX, A. S., WARRI NGTON, J. A., GARDI NER, K., BER K., NER, GARDI A., J. NGTON, WARRI S., A. LCOX, WI H IN,P .20.TeGBArcpo eefmily fam gene receptor GABAA The 2003. J. P. NG, TI WHI WEST, A. R. & GRACE, A. A. 2002. Opposite influence Opposite 2002. A. A. GRACE, & R. A. WEST, WERNER, D. F., BLEDNOV, Y. A., ARI WODOLA, O. J., SI J., O. WODOLA, ARI A., Y. BLEDNOV, F., D. WERNER, WARREN, B. L., VI ALOU, V. F., I NI GUEZ, S. D., ALCAN D., S. GUEZ, NI I F., V. ALOU, VI L., B. WARREN, WANG, J., WI LLI AMS, R. W. & MANLY, K. F. 2003. WebQ 2003. F. K. MANLY, & W. R. AMS, LLI WI J., WANG, WALSH, J. J. & HAN, M. H. 2014. The heterogeneit The 2014. H. M. HAN, & J. J. WALSH, WALLNER, M., HANCHAR, H. J. & OLSEN, R. W. 2006. Lo 2006. W. R. OLSEN, & J. H. HANCHAR, M., WALLNER, WALKER, M. C. & SEMYANOV, A. 2008. Regulation of ex of Regulation 2008. A. SEMYANOV, & C. M. WALKER, VOLKOW, N. D., FOWLER, J. S. & WANG, G. J. 2004. J. G. WANG, & S. J. FOWLER, D., N. VOLKOW, AFR,K . A IE,M . A .P,HRIDG HORRI P., Q. MA, B., M. EL, NI VAN A., K. WAFFORD, VI LLAFUERTE, S., STRUMBA, V., STOLTENBERG, S. F., Z F., S. STOLTENBERG, V., STRUMBA, S., LLAFUERTE, VI WI LSON, C. J. 2007. GABAergic inhibition in the neo the in inhibition GABAergic 2007. J. C. LSON, WI WI SDEN, W., LAURI E, D. J., MONYER, H. & SEEBURG, P. SEEBURG, & H. MONYER, J., D. E, LAURI W., SDEN, WI WOLF, M. E. & FERRARI O, C. R. 2010. AMPA recept AMPA 2010. R. C. O, FERRARI & E. M. WOLF, XI , Z. X. & STEI N, E. A. 1998. 1998. A. E. N, STEI & X. Z. , XI VI LLAFUERTE, S., HEI TZEG, M. M., FOLEY, S., YAU, W. YAU, S., FOLEY, M., M. TZEG, HEI S., LLAFUERTE, VI WI LLI AMS, R. W., BENNETT, B., LU, L., GU, J., DEFRI J., GU, L., LU, B., BENNETT, W., R. AMS, LLI WI WONG, A. C., SHETREAT, M. E., CLARKE, J. O. O. J. CLARKE, E., M. SHETREAT, C., A. WONG, YR,K,GLMIOSA . AIESA . AINSK KAMI M., EWSKA, ZANI K., OWSKA, GOLEMBI K., WYDRA, inverse agonist-preferring GABAA receptor into a di a into receptor GABAA , Chem Med agonist-preferring inverse receptor indicates that m em bers of this gene this A, of S U Sci bers em Acad m 2 a Natl m Proc that gam and 1 indicates a m gam receptor the encoding 1992. genes M. J. of KELA, SI & D. PATTERSON, J., J. WASMUTH, Curr Opin Drug Discov Devel, Discov Drug Opin Curr Neurosci, neurons: studies com bining in vivo intracellular re intracellular vivo in electrop bining and com states studies activity on neurons: activation receptor am inobutyric acid type A receptors display selectiv display receptors A type ethanol. ethanol-ins acid with ice m inobutyric am Knockin HA 2006. E. L., G. J. NER, CS, WEI HOMANI B., D. MATTHEWS, M., C. BORGHESE, 7-14. 7-14. Neurobiological sequelae of witnessi of sequelae E. NESTLER, Neurobiological L., SHEN, Q., LAPLANT, J., P. KENNEDY, erifr atics, Neuroinform functions in a m ood-related context. context. ood-related m a in functions alpha4beta3delta GABAA receptors are reversed by th by reversed are receptors Ro15-4513. GABAA alpha4beta3delta receptors. receptors. GABA A receptors and increase tonic currents in tha in currents tonic increase selective and pounds com receptors A Novel GABA 2009. J. J. LAMBERT, & D. I m pulsiveness m ediates the association be association s. the problem ediates m pulsiveness m I of im aging studies: brain circuits and treatm ent st ent treatm and circuits brain studies: aging im of 1 receptor subunit m RNAs in the rat brain. I . . I brain. rat the in RNAs Neurosci, J m subunit receptor reward anticipation are associated with genetic var . genetic with alcoholism for associated are enriched pu anticipation m I reward 2012. M. STER, BURMEI & A. R. ZUCKER, recom binant inbred m ouse strains: a powerful resour powerful a strains: e, ouse m Genom inbred binant recom A . ,B E L K N A P ,J .K .& J O H N S O N ,T .E .2 0 0 4 .G e n e t i cs repeated exposure to cocaine. cocaine. to exposure repeated GABAA receptors-an in vivo electrochem ical study. study. ical electrochem vivo in receptors-an GABAA self-adm inistration and its extinction in rats. rats. in extinction its and gl ine, dopam inistration pallidal self-adm and bal Accum 2013. M. receptors are co-localized on the presynaptic va presynaptic vitro. the in on neurons co-localized are receptors , 3-13. 3-13. J Pharm acol Exp Ther, Exp acol Pharm J 15 22 Genes Brain Behav, Brain Genes Results Probl Cell Differ, Cell Probl Results 12 37 , Proc Natl Acad Sci U S A, S U Sci Acad Natl Proc , 637-47. 637-47. 294-304. 294-304. , , 1040-62. 1040-62. 4576-80. 4576-80. Neuroscience, 1 , 299-308. 299-308. Mol Psychiatry, Mol 89 Nucleus accum bens dopam ine release m odulation by me by odulation m release ine dopam bens accum Nucleus , 5857-61. 5857-61. 6 12 Neurosci Biobehav Rev, Biobehav Neurosci 319 89 , 648-57. 648-57. , 525-31. 525-31. , 44 221-33. 221-33. , 219-27. 219-27. ng stressful events in adult m ice. ice. m adult in events stressful ng Neuroscience, 103 , 29-48. 29-48. 17 & RAYPORT, S. 1999. D1- and D2-like dopam ine ine dopam D2-like and D1- 1999. S. RAYPORT, & , 8540-5. 8540-5. , y of ventral tegm ental area neurons: Projection Projection neurons: area ental tegm ventral of y 511-9. 511-9. acid exchanges convert a diazepam -insensitive, -insensitive, diazepam a convert exchanges acid striatum . . striatum Telencephalon, diencephalon, m esencephalon. esencephalon. m diencephalon, Telencephalon, Addict Biol, Addict The addicted hum an brain viewed in the light light the in viewed brain an hum addicted The or plasticity in the nucleus accum bens after after bens accum nucleus the in plasticity or tween GABRA2 SNPs and lifetim e alcohol alcohol e lifetim and SNPs GABRA2 tween utam ate and GABA overflow during cocaine cocaine during overflow GABA and ate utam ES, J. C., CAROSONE- LI NK, P. J., RI KKE, B. B. KKE, RI J., P. NK, LI CAROSONE- C., J. ES, fam ily are often clustered in the genom e. e. genom the in clustered often are ily fam ricosities of striatal and nucleus accum bens bens accum nucleus and striatal of ricosities : new opportunities for drug developm ent. ent. developm drug for opportunities new : E, E., HERD, M. B., PEDEN, D. R., BELELLI , , BELELLI R., D. PEDEN, B., M. HERD, E., E, subunits of the gam m a-am inobutyric acid acid inobutyric a-am m gam the of subunits LBERMAN, Y., LOGAN, E., BERRY, R. B., B., R. BERRY, E., LOGAN, Y., LBERMAN, s of endogenous dopam ine D1 and D2 D2 and D1 ine dopam endogenous of s UCKER, R. A. & BURMEI STER, M. 2013. 2013. M. STER, BURMEI & A. R. UCKER, TARA, L. F., WRI GHT, K. N., FENG, J., J., FENG, N., K. GHT, WRI F., L. TARA, GER, R., WHI TI NG, P., ALTHERR, M. R., R., M. ALTHERR, P., NG, TI WHI R., GER, H. 1992. The distribution of 13 GABAA GABAA 13 of distribution The 1992. H. 282C rategies. rategies. Brain Res, Brain e alterations in behavioral responses to to responses behavioral in alterations e lsiveness and insula activation during during activation insula and lsiveness Y., MAJCZENKO, K., ZUBI ETA, J. K., K., J. ETA, ZUBI K., MAJCZENKO, Y., lam us. us. lam TL: web-based com plex trait analysis. analysis. trait plex com web-based TL: cordings and reverse m icrodialysis. icrodialysis. m reverse and cordings azepam -preferring GABAA receptor. receptor. GABAA -preferring azepam A, K., FERRARO, L., FUXE, K. & FI LI P, P, LI FI & K. FUXE, L., FERRARO, K., A, iants in GABRA2 in a fam ily sam ple ple sam ily fam a in GABRA2 in iants Prog Brain Res, Brain Prog ce for com plex trait analysis. analysis. trait plex com for ce iaiiyb xrsnpi AA ) A) GABA( extrasynaptic by citability 35 J. & BOLANOS-GUZMAN, C. A. 2013. 2013. A. C. BOLANOS-GUZMAN, & J. ly enhance delta subunit containing containing subunit delta enhance ly niieapa-otiiggmma- m gam alpha1-containing ensitive hysiological properties of striatal striatal of properties hysiological 18 , Hum an chrom osom al localization localization al osom chrom an Hum 101-108. 101-108. , e behavioral alcohol antagonist antagonist alcohol behavioral e 185-211. 185-211. RRI SON, N. L., HARRI S, R. A. & & A. R. S, HARRI L., N. SON, RRI erpamacology, Neuropharm , 307-24. 307-24. t r u c t u r eo ft h eL X Sp a n e lo f erpamacology, Neuropharm 798 w-dose alcohol actions on on actions alcohol w-dose , 156-65. 156-65. 160 Biol Psychiatry, Biol , 91-110. 91-110. 56 47 Suppl Suppl 47 , solim bic bic solim 182-9. 182-9. a m Mam 73 J J ,

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This YANG, B. Z., HAN, S., KRANZLER, H. R., FARRER, R., H. KRANZLER, S., HAN, Z., B. YANG, ZHOU, H. Y., CHEN, S. R., BYUN, H. S., CHEN, H., LI H., CHEN, S., H. BYUN, R., S. CHEN, Y., H. ZHOU, ZI NN-JUSTI N, A. & ABEL, L. 1999. Genom e search e Genom 1999. L. ABEL, & A. N, NN-JUSTI ZI YANG, A. R., LI U, J., YI , H. S., WARNOCK, K. T., WA T., K. WARNOCK, S., H. , YI J., U, LI R., A. YANG, XI AO, C., ZHOU, C., LI , K. & YE, J. H. 2007. Presyn 2007. H. J. YE, & K. , LI C., ZHOU, C., AO, XI

rtoyi laaeo +-C-ctasotr2i pa im cotransporter-2 pain. Cl- - K+ of neuropathic cleavage ethyl-D-aspartate N-m 2012. proteolytic L. H. PAN, & K. A. SOOD, pairwise correlation linkage m ethod: interesting fi interesting ethod: m iol, linkage Epidem correlation pairwise transm ission to dopam inergic neurons in in neurons inergic Physiol, dopam to ission transm Search of its Molecular Target via the GABA(A) Rece GABA(A) the via Target H. Molecular JUNE, & its L. of AN, AURELI Search W., EGHART, SI A., , ELNABAWI Autosom al linkage scan for loci predisposing to com to predisposing loci for substances. scan linkage al Autosom 580 17 Suppl 1 Suppl 17 , Am J Med Genet B Neuropsychiatr Genet, Neuropsychiatr B Genet Med J Am 731-43. 731-43. ilCe , Chem Biol J , S421- 6. 6. S421- 287 , 33853-64. 33853-64. L. A., ELSTON, R. C. & GELERNTER, J. 2012. 2012. J. GELERNTER, & C. R. ELSTON, A., L. the ventral tegm ental area of young rats. rats. young of area ental tegm ventral the for alcohol dependence using the weighted weighted the using dependence alcohol for aptic GABAA receptors facilitate GABAergic GABAergic facilitate receptors GABAA aptic , L., HAN, H. D., LOPEZ-BERESTEI N, G., G., N, LOPEZ-BERESTEI D., H. HAN, L., , NG, M., JUNE, H. L., JR., PUCHE, A. C., C., A. PUCHE, JR., L., H. JUNE, M., NG, ptor. ptor. 159B ndings on chrom osom e 4. 4. e osom chrom on ndings irs spinal chloride hom eostasis in in eostasis hom chloride spinal irs L., SR. 2011. Binge Drinking: I n n I Drinking: Binge 2011. SR. L., Front Neurosci, Front receptor- and calpain-m ediated ediated calpain-m and receptor- orbid dependence on m ultiple ultiple m on dependence orbid , 361-9. 361-9. 5 , 123. 123. Genet Genet J Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Figure 2. Chromosomal locations of major GABA locations Figure 2. Chromosomal Figure 1. The relative expression of GABA expression relative Figure 1. The Figure Legends A sagittalA section of a rodent brain illustrating Figure 3. Synapticand extra-synaptic GABA GABRB1; GABRB1; members of the (Bz) site is similarly formed by the N-terminal is formed by similarly extracell (Bz) site the N-terminal transmembrane region oftransmembrane the region subunit interface. putative A binding site fo may be substituted by a large domainsextracellular betweenlarge the families, named named families, anions. that are arranged to formcentral a ion ch simplified model of the receptor. of the model simplified this circuit theare principal excitatory (green following genes: arrangement of the withingenes en them designates prientationthe along chromosome. clusteThese chromosomesmouse in on(shown humanchromosomes and the four figure shows clusters gene main an inindividual clusters present are subunitsconserved acr extra-synaptic GABA θ, θ, subunit genes are shown in red, GABA GABRQ. arrowsBlack indicate the direction A receptor subunit families are subunit families yellow. The su shownreceptor in

The The majority of proteins making up the complex fr come β 2, GABRB2; α α α (1-6), (1-6), family, two 1, GABRA1; 1, A receptor isoforms throughout the the isoforms receptor throughout β 3, GABRB3; GABRB3; 3, β subunit. (G) bindingThe GABA sites formed are by the (1-3) and (1-3) α subunit. subunit. β α β , and, one 2, GABRA2; GABRA2; 2, subunit genes blue,are subunit genes GABA γ (1-3). Most commonly (1-3). made are receptors of two 1, GABRG1; GABRG1; 1, A A α and receptors are made are receptors up of five protein subunits, γ A d their relative locationsd their relative on humanand mouse sfrsi h eadcruty R isoforms reward the in circuitry. annel permeabletochloride and bicarbonate subunit although in somecases the A α r the neurosteroids (N) is shown within the ther within the neurosteroids (N) is shown coding theindividual subunitsdisplayed. of transcriptionfor the individual genes. receptor isoforms in rodent brain and a rodenta brainisoforms in and receptor the expressionprofile of both synaptic and 3, GABRA3; GABRA3; 3, ), inhibitory (red) and dopaminergic (blue) (blue) dopaminergic and (red) inhibitory ), β subunit interface and the benzodiazepine A receptorgene clusters. γ 2, GABRG2, ular domains between the ular domains between reward circuitry. Depicted within γ subunit genes are green. Other green.are Other genes subunit oss mammalian The genomes. oss α 4 GABRA4; GABRA4; 4 bunits are encoded by the rs are expanded and the expandedare and the rs γ 3, GABRAG3; GABRAG3; 3, om 3 related subunit red). The red arrow red). arrow The red α 5, GABRA5; GABRA5; 5, The genes for for The genes N-terminal ε, subunit α GABRE; and β 1, 1, α

Figure 4. Postulated influence of Figure influence Postulated 4. Herman et al., 2013). Similarly, note that the VTAin Similarly, et 2013). Herman al., but a discussionamygdala not are displayed example, in the NAcc, expressed in a mannerneuron-specific thro α this pool, a prop extrasynaptically Of on MSNs. immunohistochemical andelectrophysiologicalimmunohistochemical(se studies expressed in the NAcc. For simplicity, GABA projections. The reported expression of GABA related,behavioural broad constructs (Janssen et al., 2009, Santhakumar et al., 2010). See als See 2010). al., et Santhakumar 2009, (Janssen al.,et their however, developmentalwhere, al., 2008), express of of (Tan et al., 2010, Okada et al., al., Okada et (Tan al., 2010, et selectively expressed in GABAergic interneurons and do 2007). 2007). been described for VTA GABAergic interneurons 5 subunit (Lingford-Hughes et al., et Mende subunit5 2012, (Lingford-Hughes α A) B) 5-containing GABA

Shows normal conditions of Shows the susceptible brain because of GABRA2 because brain susceptible the Shows motivation to take the drug motivation behavi to take drugs. These inby weakness parentalis facilitated moni hypothesised reduction of function.GABA A tendency tow brain brain drug.the The negative sign(-) denotes the inh general control delinquent over behaviour, and pote A R isoforms responsible for mediating andphasic tonic in A Rs has alsoRs reportedbeen fortheMSNsdorsal of striatum in addition to the in addition 2004). A population of extrasynaptic of extrasynaptic population A 2004). non-susceptible brain. α 2-GABA A A control on receptor activation of addiction- R isoforms in expressed oural aspectsoural weaken the control over ortion suggestedbeen has to incorporate the ughout the mesolimbicFor neurocircuitry. can be found in (Marowsky et al., 2012, 2012, (Marowsky found inbe al., et can z et al.,z et 2013). localization An extrasynaptic toring, leading toreduction of over control toring, α ntiates controlmotivation over to take (Vashchinkina al., et Xiao et 2012, al., 4 A R subtypes is derived from both β o Fig 5 for detail for5 detail on GABAo Fig risk variants risk which present leadto a subtype, e text). e α ion beenhas in debatedrodents paminergic neurons respectively α 2-GABA 1 ibitory effectsof GABA in the β 2 and2 ards delinquentards behaviour A α R activation allows α 4 various regions of the x β α β 3 receptors has also 2 are expressed are 2 β 2 subtypes2 are hibition are A R isoforms R isoforms (Ade et (Ade Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Figure 5. Synaptic and extra-synaptic GABA (Note: We speculatively ascribe to GABA a role speculatively We (Note: ascribe likely to target synaptic receptors whereas to whereas synaptic to receptors target likely inputs from on largely the VTA, their dendritic (se tree glutamatergicinputs fromnumber a of limb MSN dendrites. MSNs can inhibit each other via spiking interneurons, whichare coupled via gap juncti parvalbumin-containing FSIs, giving to rise feed a powerful MSNs receive (FSIs). i Interneurons Spiking 2015). Changes in lateral inhibition, due to decreased inhibition, in lateral Changes 2015). respectively although this has view been rece receptors. mediated actions DA are by D1Ra yale l,21) Lydall et al., 2011). Rang 1997, Bauer, EEGs and (Costa inmeasured might be 2015)) al., et (Lieberman rs279858 SNP or humans (dep 2013)) life (Lambert, stress, early NAcc core neurocircuitry andthe GABA expression and EEG the withsubjective effects of drugs includingpsychostim motivationbetween and drug-taking, on the ba interneurons of the andNAcc effect the of β power. A receptor isoforms expressed inthe MSNs andFast- early-life stress and identified SNPs upon their ic and forebrainregions and dopaminergic nd D2R on anddirect indirect pathway MSNs nic DA firingnicmayaffect DA ntly challengesfor the NAcc (Kupchik et al., -forwardinhibition (FFI). Additionally, fast- aswamy et al., 2004, Edenberg 2002, et al., et aswamy lateralinhibition (LI) powerful and receive the basis for the increased beta power beta power the increased for basis the A endent on specific GABRA2 variants e.g. variants endent on GABRA2 specific sis of the association of GABRA2 variants R isoforms expressed in the and MSNs A ulants and alcohol). receptors in modulating the output ons, send a much inputweaker to nhibitoryinputontheir soma from α e Fige for 3 details). Burstfiring DA is 2 GABA 2 A R in rodents (as a result of largelyextrasynaptic Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Figure 1 α 2 2/3 2 α α 3 1 n 2 2 2 3 α 2 α n 5 1 others 3 α α α 6 6 2 4 n 3 n n δ δ 2

βγ α G G G G N Cl N G G α G G - β

Accepted Article This article is protected by copyright. All rights reserved. rights All by copyright. protected is article This Figure 2 Human chromosome X chromosome Human Mouse chromosome 11 chromosome Mouse 5 chromosome Human Mouse chromosome 5 chromosome Mouse 4 chromosome Human Mouse chromosome 7 chromosome Mouse 15 chromosome Human Mouse chromosome X chromosome Mouse GABRE G GABRE GABRG1 GABRA2 COX7B2 GA COX7B2 GABRA2 GABRG1 GABRB2 GABRA6 GABRA6 GABRB2 GABRB3 GABRA5 GABRA5 GABRB3 ABRA3 GABRQ GABRQ ABRA3 GABRA1 GABRG2 GABRG2 GABRA1 BRA4 GABRB1 GABRB1 BRA4 GABRG3 GABRG3

e e s s 4 4 ptible brai usceptible

GAB R n n brain brain A 2 geneti c variants s variants u pport con ditions ofditions r isk toisk drug abuse abuse