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2013-04-30

Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence

Linzy M. Hendrickson University of Massachusetts Medical School

Et al.

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Repository Citation Hendrickson LM, Guildford M, Tapper AR. (2013). Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.3389/fpsyt.2013.00029. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/67

This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in University of Massachusetts Medical School Faculty Publications by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. REVIEW ARTICLE published: 30 April 2013 PSYCHIATRY doi: 10.3389/fpsyt.2013.00029 Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence

Linzy M. Hendrickson, Melissa J. Guildford and Andrew R.Tapper*

Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA

Edited by: Alcohol and nicotine are often co-abused. As many as 80–95% of alcoholics are also smok- Nicholas W. Gilpin, Louisiana State ers, suggesting that ethanol and nicotine, the primary addictive component of tobacco University Health Sciences Center New Orleans, USA smoke, may functionally interact in the central nervous system and/or share a common Reviewed by: mechanism of action. While nicotine initiates dependence by binding to and activating Shaolin Wang, University of Virginia, neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels normally USA activated by endogenous acetylcholine (ACh), ethanol is much less specific with the ability Darlene H. Brunzell, Virginia to modulate multiple gene products including those encoding voltage-gated ion chan- Commonwealth University, USA Shafiqur Rahman, South Dakota State nels, and excitatory/inhibitory neurotransmitter receptors. However, emerging data indicate University, USA that ethanol interacts with nAChRs, both directly and indirectly, in the mesocorticolim- *Correspondence: bic dopaminergic (DAergic) reward circuitry to affect brain reward systems. Like nicotine, Andrew R. Tapper, Department of ethanol activates DAergic neurons of the ventral tegmental area (VTA) which project to Psychiatry, Brudnick Neuropsychiatric the nucleus accumbens (NAc). Blockade of VTA nAChRs reduces ethanol-mediated acti- Research Institute, University of Massachusetts Medical School, 303 vation of DAergic neurons, NAc DA release, consumption, and operant responding for Belmont Street, Worcester, MA ethanol in rodents. Thus, ethanol may increase ACh release into the VTA driving activation 01604, USA. of DAergic neurons through nAChRs. In addition, ethanol potentiates distinct nAChR sub- e-mail: andrew.tapper@ type responses to ACh and nicotine in vitro and in DAergic neurons.The smoking cessation umassmed.edu therapeutic and nAChR partial agonist, varenicline, reduces alcohol consumption in heavy drinking smokers and rodent models of alcohol consumption. Finally, single nucleotide polymorphisms in nAChR subunit genes are associated with alcohol dependence pheno- types and smoking behaviors in human populations. Together, results from pre-clinical, clinical, and genetic studies indicate that nAChRs may have an inherent role in the abusive properties of ethanol, as well as in nicotine and alcohol co-dependence.

Keywords: nicotine, alcoholism, acetylcholine, nicotinic receptors, mesolimbic dopamine system

INTRODUCTION basis of the high rates of nicotine and alcohol co-abuse. For exam- Alcoholism is the third leading cause of preventable mortality in ple, it is possible that alcohol use leads to nicotine use or vice versa the world (Mokdad et al., 2004). Worldwide, about 2 billion people (Tyndale, 2003), or that because alcohol and nicotine are legal consume alcohol, with 76.3 million who have diagnosable alco- and readily available, the likelihood of their co-use is increased hol use disorders (AUDs). Additionally, when analyzing the global (Funk et al., 2006). However, mounting genetic, pre-clinical, and burden of this disease, alcohol causes 2.5 million deaths per year clinical evidence indicates that neuronal nicotinic acetylcholine (4% of the worldwide total) (World Health Organization, 2011). receptors (nAChRs), the molecular targets of nicotine that initiate The estimated economic cost of alcoholism in the US alone, due dependence in smokers, may also contribute to alcohol’s abusive to health care costs as well as productivity impacts such as lost properties. In addition, neuronal nAChRs may represent common wages, was $220 billion in 2005, which was significantly higher molecular targets where nicotine and ethanol functionally inter- than cancer ($196 billion) or obesity ($133 billion) (CASA, 2000). act, potentially explaining the widespread co-morbidity between Interestingly, several reports from the 1980s to 1990s have esti- smoking and alcohol consumption. The focus of this review is mated that 80% of alcohol-dependent people are also smokers to highlight this evidence, summarize recent findings, and iden- (Bobo, 1992; Miller and Gold, 1998) and that smokers have an tify gaps in knowledge regarding the role of nAChRs in alcohol increased risk of developing AUDs (DiFranza and Guerrera, 1990; dependence and nicotine and alcohol co-abuse. Grant et al., 2004). In addition, while the smoking rates in the gen- eral population of the U.S. have dramatically decreased over the NEURONAL nAChRs past two decades, smoking has remained high in alcoholic individ- Neuronal nAChRs are ligand-gated cation channels that are acti- uals (Meyerhoff et al., 2006), with current estimates still between vated by the endogenous neurotransmitter acetylcholine (ACh) 70 and 75% (Bobo and Husten,2000). These high rates of co-abuse and the exogenous tertiary alkaloid nicotine (Albuquerque et al., of nicotine and alcohol have led some researchers to define this 2009). They belong to the superfamily of Cys-loop ligand- population as “alcoholic smokers” as compared to “smokers” (Lit- gated ion channels that include receptors for γ-amino butyric tleton et al., 2007). Many hypotheses have been proposed as to the acid (GABA, the GABAA, and GABAC receptor), glycine, and

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5-hydroxytryptamine (5-HT3)(Le Novere and Changeux, 1995; when the Cys pair is missing (Le Novere and Changeux, 1995; Changeux and Edelstein, 1998). These ligand-gated ion channels Changeux and Edelstein, 1998). have similar structural and functional features. All subunits in this Five subunits combine to form two classes of receptors: homo- family contain a pair of disulfide-bonded cysteines separated by 13 meric receptors containing only α subunits (α7-α9) or heteromeric residues (Cys-loop) in their extracellular amino terminus (Karlin, receptors that contain α and β subunits (α2- α6 and β2-β4) (Dani 2002). and Bertrand, 2007)(Figures 1C,D). The most abundant subtypes Neuronal nAChRs, like all members of the cys-loop family of in the brain are the low affinity α7 homomeric and high affinity ligand-gated ion channels are formed by the arrangement of five α4β2∗ heteromeric nAChRs. An asterisk in nAChR nomenclature subunits to create a central pore (Albuquerque et al., 2009). The (i.e.,α4∗,α4β2∗) indicates that other unidentified nAChR subunits structure of neuronal nAChRs is homologous to muscle nAChRs may also be present and can be read as “α4 subunit containing (Karlin,2002),for which the atomic structure has been determined nAChRs.” Importantly, heteromeric nAChRs are incredibly com- from electron microscopy studies from the fish electric organ plex as they can contain two or three alpha subunits co-assembled (Torpedo nAChRs) (Miyazawa et al., 2003; Unwin, 2005). Each with two or three beta subunits. For example, α4β2 nAChRs can nAChR gene encodes a protein subunit consisting of a large amino- be formed by either two α and three β subunits [(α4)2(β2)3] or terminal extracellular domain composed of β-strands, four trans- three α and two β subunits [(α4)3(β2)2](Zwart and Vijverberg, membrane α-helices segments (M1-M4), a variable intracellular 1998; Nelson et al., 2003; Moroni et al., 2006). Each stoichiometry loop between M3 and M4, and an extracellular carboxy-terminus of the nAChR exhibits distinct sensitivity to agonist: [(α4)2(β2)3] (Corringer et al., 2000)(Figure 1A). The extracellular N-terminus nAChRs have a higher sensitivity to agonist (EC50 = ∼1 µM ACh); contains the ACh binding domain that forms a hydrophobic whereas [(α4)3(β2)2] nAChRs have a lower sensitivity to ago- pocket located between adjacent subunits in an assembled recep- nist (EC50 = ∼100 µM ACh) (Buisson and Bertrand, 2001; Nelson tor (Sine, 2002). The M2 segment of all five subunits forms the et al., 2003; Moroni et al., 2006). In addition, more than one type conducting pore of the channel, and regions in the M2 intracellu- of alpha and/or beta subunit may be present in a functional recep- lar loop contribute to cation selectivity and channel conductivity tor. For example, a subtype identified in midbrain dopaminergic (Corringer et al., 2000)(Figure 1B). (DAergic) neurons contains α4 and β2 subunits co-assembled with In vertebrates, 12 genes encoding 12 distinct neuronal nAChR α6 and β3 subunits to form the α4α6β2β3∗ nAChR (Salminen et al., subunits have been identified (Cholinergic Receptor Nicotinic 2004, 2007; Zhao-Shea et al., 2011; Liu et al., 2012). This subunit Alpha: CHRNA2-10 and Cholinergic Receptor Nicotinic Beta: diversity allows for a vast array of nAChR subtypes each with dis- CHRNB2-4 encoding α2-α10 and β2-β4 nAChR subunits, respec- tinct pharmacological and biophysical properties (McGehee and tively all of which can be found in humans and other mammals, Role, 1995; Gotti et al., 2007). except for α8 which has only been identified in avian species (Mil- Neuronal nAChRs can exist in three conformational states and lar and Gotti, 2009). Subunits are classified as either α-, by the are regulated by exposure to agonist: closed at rest, when the recep- presence of a Cys-Cys pair near the start of TM1, or non-α (β) tor has low affinity for agonist and the channel is closed; the active

FIGURE 1 | Neuronal nAChR Structure. (A) Membrane topology of a affinity for agonist. To date, only mammalian α7, α9, and α10 (not shown) neuronal nAChR subunit. Each nAChR subunit contains four subunits may form functional homomers. (D) The majority of high affinity transmembrane domains (M1-M4), an extracellular amino- and nAChRs are heteromeric and consist of a combination of α and β subunits. carboxy-terminus, and a prominent M3-M4 intracellular loop of variable Importantly, multiple α subunits may coassemble with multiple β subunits length. (B) Five subunits coassemble to form a functional subunit. (C) in the pentameric nAChR complex (illustrated here by α4α6β3β2). ACh Homomeric receptors consist of α subunits only and usually have low binding sites are depicted as red triangles.

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state, when agonist occupies the ligand binding site and the chan- as GABAA and glycine receptors (Borghese et al., 2003a). Addi- nel is open allowing cations to flow down their electrochemical tionally, it is possible that the ethanol-induced inhibitory effect gradient; and the desensitized state, when the channel is occluded seen with α7 nAChRs is due to the inherently fast desensitization and the receptor is unresponsive to ligand (Dani and Bertrand, rate of these receptors, implying that ethanol inhibition results 2007; Albuquerque et al., 2009). in enhanced desensitization (Dopico and Lovinger, 2009). Thus, Interestingly, while nAChRs mediate fast, direct synaptic trans- these and in vivo studies discussed below, suggest that ethanol mission at neuromuscular junctions and autonomic ganglia, there modulation of nAChRs, either by enhancing or inhibiting func- are very few examples of fast nicotinic transmission in the mam- tion, may contribute to (1) the inherent mechanism of action of malian brain (Dani and Bertrand, 2007). However, neuronal ethanol reward and (2) the common co-abuse of nicotine and nAChRs are expressed at the soma in neurons where they pre- alcohol. sumably modulate excitability directly. In addition, a significant proportion of nAChRs are located on presynaptic terminals (Role NEURONAL nAChR EXPRESSION IN THE and Berg, 1996) where they facilitate Ca2+ dependent release of MESOCORTICOLIMBIC DA PATHWAY neurotransmitters (McGehee et al., 1995; Wonnacott, 1997). This Although neuronal nAChRs are expressed throughout the CNS, may occur indirectly as a result of Na+ influx causing mem- most studies focusing on the role of nAChRs in addiction have brane depolarization and activation of voltage-gated Ca2+ chan- examined the mesocorticolimbic “reward” circuitry. Indeed, it nels or directly through Ca2+ influx through the channel itself is widely accepted that the mesocorticolimbic dopamine system (Albuquerque et al., 2009). plays a central role in modulating the rewarding effects of drugs of abuse (Wise and Bozarth, 1987; Koob, 1992). ETHANOL MODULATION OF NEURONAL nAChRs: IN VITRO The ventral tegmental area (VTA) is located in the ventral STUDIES midbrain, medial to the substantia nigra, and ventral to the red While ethanol modulates several ligand-gated ion channels includ- nucleus. It is referred to as an “area” and not considered to be a ing GABAA, NMDA, and 5-HT3 receptors (For a review see “nucleus” because the cryoarchitecture of the region is not well Spanagel, 2009), ethanol also potently modulates nAChRs at low defined such that the boundaries of the VTA are determined by its concentrations of ethanol (100 µM–10 mM), identifying nAChRs neighboring structures (Fields et al., 2007; Ikemoto, 2007). Within as potential targets for ethanol action (Nagata et al., 1996). In het- the VTA are two main cell populations, DAergic projection neu- erologous expression systems, the effect of ethanol on nAChRs rons, which comprise ∼60% of cells in this region (Swanson, depends on the subunit composition of the nAChR. Expres- 1982), as well as local GABAergic interneurons and projection sion of different combinations of human neuronal nAChR alpha neurons (Carr and Sesack, 2000; Margolis et al., 2006a). The and beta subunits in Xenopus oocytes, indicate acute ethanol VTA receives inputs from regions throughout the CNS (Geisler (75 mM) potentiates ACh-induced current of α2β4, α4β4, α2β2, and Zahm, 2005) including glutamatergic projections from the and α4β2 nAChRs while lower concentrations of ethanol (20– prefrontal cortex (PFC) (Sesack and Pickel, 1992), as well as 50 mM) inhibits nicotine-induced current of α7 nAChRs and all glutamatergic, cholinergic, and GABAergic projections from two concentrations of ethanol tested have no effect on α3β2 or α3β4 groups of mesopontine tegmental area neurons, the pedunculo- nAChRs (Cardoso et al., 1999). Similar ethanol effects on heterol- pontine tegmental nucleus (PPTg) and the laterodorsal tegmental ogous expression of rat nAChRs in Xenopus oocytes have been nucleus (LDT; Figure 2A)(Cornwall et al., 1990; Semba and observed except that ethanol could potentiate or inhibit α3β4 Fibiger, 1992; Oakman et al., 1995). Other regions projecting to nAChRs at all ethanol concentrations tested likely reflecting oocyte the VTA include the nucleus accumbens (NAc), amygdala, ven- batch to batch variability. In cultured rat cortical neurons, ACh- tral pallidum, superior colliculus, and lateral hypothalamus (For evoked nAChR currents insensitive to α-bungarotoxin (α-Bgtx), a review see Fields et al., 2007). Additionally, the lateral habenula which blocks α7 nAChRs (i.e., heteromeric nAChRs) are signif- (LH), a small nucleus that is a part of the epithalamus, has been icantly enhanced by physiologically relevant concentrations of shown to project to midbrain areas, and modulate the release of ethanol while nAChRs sensitive to α-Bgtx (i.e., α7 homomeric DA from theVTA and substantia nigra pars compacta (Herkenham nAChRs) are inhibited (Aistrup et al., 1999). Although not tested and Nauta, 1979; Ji and Shepard, 2007; Matsumoto and Hikosaka, directly the α-Bgtx insensitive current profile was most similar to 2007). native α4β2∗ nAChRs (Marszalec et al., 1999). Neurons in theVTA primarily project to the ventromedial stria- Similar to other ligand-gated ion channels,ethanol potentiation tum including the NAc shell and core as well as smaller projections of nAChRs is hypothesized to be a result of the ethanol-induced to the PFC, hippocampus, entorhinal cortex, and lateral septal stabilization of the open channel state of the receptor (Wu et al., areas (Fields et al., 2007). Furthermore, studies using retrograde 1994; Forman and Zhou, 1999; Zuo et al., 2004). Site directed cys- markers have shown that distinct groups of neurons originating teine mutagenesis and covalent labeling with sulfhydryl reagents in the VTA project to specific forebrain regions (Fallon et al., 1984; indicate that amino acid residues in the pore forming M2 region of Margolis et al., 2006b). Projections to the NAc contain the largest neuronal nAChR at least partly contribute to the ethanol binding proportion of DA neurons, with 65–85% being DAergic, while the pocket (Borghese et al., 2002, 2003a,b). While individual amino PFC projections are only 30–40% DAergic (Swanson, 1982; Fal- acid residues forming the ethanol binding pocket may be distinct lon et al., 1984). The remaining component of VTA afferents to from other cys-loop receptors, the overall motif, the extracellular the NAc and PFC contain GABAergic neurons (Carr and Sesack, domain of M2, is critical for ethanol actions on nAChRs as well 2000). The VTA is not a homogeneous region and can be divided

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FIGURE 2 | Neuronal nAChR expression in the reward pathway. (A) addition, ethanol potentiates ACh activation at high affinity α4β2* Sagittal rodent section illustrating the simplified mesocorticolimbic and nAChRs (red plus sign). The effect of alcohol on additional nAChRs in habenulo-peduncular circuitry. Known neuronal nAChR subtypes the VTA is unknown. This confluence of events in combination with expressed in different nuclei are indicated [for a review see (Millar and other effects of alcohol in the VTA ultimately increases DA release in Gotti, 2009)]. (B) In the VTA, alcohol stimulates DAergic neurons at NAc (red arrow). VTA, Ventral tegmental area; NAc, Nucleus least, in part, via nAChR activation. Ethanol increases ACh release (red accumbens; PFC, Prefrontal cortex; LH, Lateral habenula; MH, Medial arrow, presumably through cholinergic projection from the LDT/PPTg) habenula; IPN, Interpeduncular nucleus; LDT, Lateral dorsal which in turn activates nAChRs on DAergic neurons driving activity. In tegmentum; PPTg, Pedunculopontine tegmentum. into three sub-regions, the anterior VTA, posterior VTA, and the NEURONAL nAChRs AND ETHANOL: IN VIVO STUDIES tail VTA. Additionally, evidence indicates that each region may The rewarding or reinforcing properties of ethanol and nicotine, project to distinct regions of the striatum and may also respond as with most drugs of abuse, are associated with an increase in differently to drugs of abuse including nicotine and ethanol (Rodd DA release in the NAc (Di Chiara and Imperato, 1988; Lewis et al.,2004a,2010; Ikemoto,2007; Shabat-Simon et al.,2008; Zhao- and June, 1990; Benwell and Balfour, 1992; Samson et al., 1992; Shea et al., 2011). Importantly, nAChRs are robustly expressed in Diana et al., 1993; Weiss et al., 1993; Lanca, 1994; Pontieri et al., theVTA.DAergic neurons contain several nAChR subtypes includ- 1996). Both drugs increase the baseline firing frequency of VTA ing α4β2∗, α4α5β2∗, α4α6β2∗, α6β2∗, α3β2∗, and α7 (Picciotto DAergic neurons and also increase the firing pattern from pha- et al., 1998; Champtiaux et al., 2002; Marubio et al., 2003; Grady sic to bursting, facilitating NAc DA release (Mereu et al., 1984; et al., 2007; Gotti et al., 2010; Zhao-Shea et al., 2011; Liu et al., Gessa et al., 1985; Foddai et al., 2004; Exley et al., 2011; Li et al., 2012); whereas GABAergic VTA neurons express α4β2, α7, and 2011). Although the precise role of NAc DA release in reward is α3β4 nAChRs (Figure 2A)(Klink et al., 2001; Mansvelder et al., still under debate (Schultz, 2004; Salamone and Correa, 2012), 2002; Pidoplichko et al., 2004; Nashmi et al., 2007; Tolu et al., ethanol- and nicotine-induced release of DA is critical for the 2012). onset and maintenance of dependence. Pharmacological blockade

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of DA receptors, destruction of DA neurons or lesioning of the validity as patients administered mecamylamine report reduced NAc reduces ethanol and nicotine self-administration (Kiianmaa, pleasurable effects of alcoholic beverages (Chi and de Wit, 2003). 1978; Koob and Weiss, 1990; Corrigall and Coen, 1991; Corri- As discussed above, ethanol is not a direct agonist at nAChRs; gall et al., 1992, 1994; Rassnick et al., 1993; Ikemoto et al., 1997). rather it potentiates or inhibits nAChRs depending on subtype. In addition, rats will self-administer ethanol or nicotine directly Thus, nAChR involvement in ethanol reward implies that ethanol into the VTA (Gatto et al., 1994; Ikemoto et al., 2006), and more must increase ACh concentrations in brain regions involved in specifically, the posterior VTA (Rodd et al., 2004b). reward/reinforcement. To date, one study has measured extracel- It is becoming increasingly clear that nicotine dependence is lular concentrations of ACh in the VTA of rats that voluntarily initiated by activation of DAergic neurons via nAChRs contain- consumed ethanol and found that ACh levels were increased after ing α4 and β2 subunits with some contribution of α6∗ nAChRs ethanol consumption and shortly thereafter, DA concentrations (Picciotto et al., 1998; Tapper et al., 2004; Maskos et al., 2005; were elevated in the NAc as well (Larsson et al., 2005). These data Pons et al., 2008; Exley et al., 2011; Tolu et al., 2012). In the indicate that the increase in VTA ACh could drive activation of context of this review, we will not focus further on the mecha- DAergic neurons through nAChRs (Figure 2B). While the pre- nistic bases of nicotine dependence; rather we direct readers to dominant VTA cholinergic afferents project from the PPTg and a recent review article (De Biasi and Dani, 2011). In contrast LDT area (Oakman et al., 1995), brain regions that have also been to nicotine, multiple mechanisms underlying ethanol-mediated implicated in mediating natural as well as drug-reward behavior activation of VTA DAergic neurons have been proposed includ- (Yeomans et al., 1993), additional experiments will be needed to ing modulation of intrinsic ion channels within these neurons, as verify that these inputs mediate ethanol-induced increases in VTA well as ethanol-mediated alterations in synaptic input, both exci- ACh. In addition, the mechanism by which ethanol could elicit an tatory and inhibitory (Okamoto et al., 2006; Job et al., 2007; Xiao increase in ACh release into the VTA is unknown and warrants and Ye, 2008; Xiao et al., 2009; Rodd et al., 2010; Theile et al., further study. 2011; Guan et al., 2012). However, cholinergic signaling through nAChRs also contributes to NAc DA release and ethanol rein- NEURONAL nAChRs AND ALCOHOL: IDENTIFYING RELEVANT forcement (Blomqvist et al., 1992, 1993, 1996; Ericson et al., 1998; SUBTYPES: PHARMACOLOGY Nadal et al., 1998; Dyr et al., 1999; Le et al., 2000; Soderpalm Because mecamylamine blocks virtually all subtypes of nAChRs, it et al., 2000; Farook et al., 2009a; Kuzmin et al., 2009). One of the provides little insight into the subunit composition of key nAChRs most consistent findings implicating nAChRs in ethanol behav- involved in ethanol activation of DAergic neurons or ethanol iors associated with reward/reinforcement is that the non-specific behaviors associated with the VTA such as consumption. Thus, nAChR antagonist, mecamylamine, reduces ethanol consumption several studies have used additional, more selective nAChR antag- and blocks ethanol-induced DA release in the NAc. Originally dis- onists, in an effort to uncover the nAChR subtype(s) that may covered by pioneering work of Soderpalm and Engel, systemic be involved in ethanol’s mechanism of action (Table 1). Studies mecamylamine significantly reduces ethanol-mediated extracel- in VTA responses to nicotine indicate that DAergic neurons con- lular DA release in the NAc (Blomqvist et al., 1993), and reduces tain several nAChR subtypes including α4β2∗, α4α5β2∗, α4α6β2∗, ethanol consumption in rats (Blomqvist et al., 1996). The effect α6β2∗, α3β2∗, and α7 (Picciotto et al., 1998; Champtiaux et al., of mecamylamine is localized to the VTA, as local infusion of 2002; Marubio et al., 2003; Grady et al., 2007; Gotti et al., 2010; the antagonist in rat midbrain but not NAc reduces NAc DA Zhao-Shea et al., 2011; Liu et al., 2012). Identifying the precise release elicited by ethanol (Blomqvist et al., 1997). VTA infusion subunit composition of nAChRs involved in ethanol consump- of mecamylamine also reduces rat operant responding for ethanol tion and activation of VTA DAergic neurons is challenging due to and ethanol-associated cues,as well as consumption during relapse the sheer number of potential subunit combinations that may be (Lof et al., 2007; Kuzmin et al., 2009). In mice, mecamylamine expressed in the VTA. However, identifying one or more nAChR delivered systemically reduces ethanol consumption in C57Bl/6J subtypes involved in ethanol activation of VTA and/or reward may mice in the restricted access ethanol consumption “drinking in lead to novel targets to reduce consumption. Systemic injection or the dark” (DID) paradigm (Hendrickson et al., 2009), a model VTA infusion of the competitive α4β2 nAChR antagonist,dihydro- of binge drinking (Rhodes et al., 2005, 2007), as well as in the β-erythroidine (DHβE), in rats, fails to reduce ethanol-mediated two-bottle choice consumption assay (Farook et al., 2009a). What DA release in the NAc and ethanol intake (Ericson et al., 2003; is mecamylamine’s mechanism of action in reducing ethanol con- Chatterjee et al., 2011). In addition, low doses of DHβE also have sumption? In mice, mecamylamine apparently blocks activation of little effect on operant responding for ethanol in rats, although VTA DAergic neurons by ethanol as measured by c-Fos induction a higher dose can reduce responding (Kuzmin et al., 2009). Sys- after challenge with an intraperitoneal injection (i.p.) of ethanol temic injection of DHβE does not reduce consumption in mice as (Hendrickson et al., 2009). More recently, it has been demon- measured in the DID assay nor ethanol-induced NAc DA release strated that mecamylamine blocks ethanol-mediated activation of (Larsson et al., 2002; Hendrickson et al., 2009). Together these data VTA DAergic neurons in mouse midbrain slices (Liu et al., 2013). suggest that α4β2 nAChRs may not be critical for ethanol reward Mecamylamine also blocks the ability of ethanol to condition a and consumption behavior. However, sensitivity of α4β2∗ nAChR place preference in mice (Bhutada et al., 2012). Thus, these data blockade by DHβE is dependent on the stoichiometry of the recep- suggest that nAChR expressed in the VTA contribute to ethanol tor and the expression of other non-α4β2 subunits that may also activation of DAergic neurons and ethanol reward. The effects of be present in an α4β2∗ nAChR complex (Harvey and Luetje, 1996; mecamylamine in these pre-clinical models may have predictive Harvey et al., 1996; Le et al., 2000; Larsson et al., 2002; Ericson

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Table 1 | Neuronal nAChR ligands that modulate alcohol behaviors.

Drug nAChR subtype target Route of delivery Effect on ethanol behavior (in rodents)

Mecamylamine Non-selective antagonist i.p. Decreased ethanol intake in rats (Blomqvist et al., 1996) i.p. Decreased ethanol intake in mice (Hendrickson et al., 2009) i.p. Blocked ethanol-induced DA release in NAc in rats (Blomqvist et al., 1993) i.p. Partially counteracted ethanol-induced enhancements of locomotor activity and brain DA turnover in mice (Blomqvist et al., 1992) i.p. Blocked ethanol-induced activation of DA neurons in mice (Hendrickson et al., 2009) i.p. Reduced operant self-administration and blocked deprivation-induced increase in alcohol consumption in rats (Kuzmin et al., 2009) VTA Reduced ethanol-induced accumbal DA release in rats (Ericson et al., 1998) i.p. Reduced ethanol intake in rats (Le et al., 2000)

Nicotine Agonist s.c. (chronic) Increased ethanol intake in rats (Potthoff et al., 1983; Le et al., 2000) s.c. (subchronic/acute) Increased ethanol intake in rats (Blomqvist et al., 1996; Le et al., 2000) s.c. (subchronic) Increased ethanol preference in rats (Blomqvist et al., 1996) s.c. (acute) Enhanced ethanol-induced locomotor stimulation in mice (Blomqvist et al., 1992) s.c. (subchronic) Enhanced ethanol-induced locomotor stimulation in rats (Blomqvist et al., 1996) s.c. (subchronic) Enhanced DA turnover-increasing effect of ethanol in rats (Johnson et al., 1995) s.c. (chronic) Decreased ethanol intake in rats (Sharpe and Samson, 2002) s.c. (chronic) Decreased ethanol seeking in rats (Sharpe and Samson, 2002) i.p. (acute) Decreased ethanol intake in mice (Hendrickson et al., 2011)

Varenicline α4β2 Partial agonist high i.p. and VTA Decreased ethanol intake in mice (Hendrickson et al., 2010; Kamens et al., affinity α3β2, α3β4, α6*, α7 2010; Santos et al., 2012) low affinity binding i.p. Decreased ethanol intake in rats (Steensland et al., 2007) i.p. Reduced ethanol seeking and consumption with no rebound increase in ethanol after cessation in rats (Steensland et al., 2007) i.p. Reduced operant ethanol self-administration and blocked deprivation-induced relapse-like consumption in rats (Kuzmin et al., 2009) s.c. Blocks increase in extracellular DA in NAc following acute ethanol injection in rats (Ericson et al., 2009) α-Conotoxin MII α6*, α3β2* Antagonist VTA Reduced alcohol-induced DA release in mice (Larsson et al., 2004) VTA Reduced locomotor stimulation in mice (Larsson et al., 2004) VTA Decreased self-administration of ethanol in rats (Kuzmin et al., 2009) VTA Blocked deprivation-induced relapse-like ethanol consumption in rats (Kuzmin et al., 2009)

DHβE α4β2* antagonist s.c. No effect on ethanol consumption in rats (Le et al., 2000) s.c. No effect on DA-enhancing effect of ethanol in mice (Larsson et al., 2002) i.p. Inhibited ethanol intake at 4mg/kg in rats (Kuzmin et al., 2009) s.c. No effect on ethanol consumption in rats (Chatterjee et al., 2011)

MLA α7* antagonist i.p. No effect on DA-enhancing effect of ethanol in mice (Larsson et al., 2002) i.p. No effect on self-administration of ethanol or deprivation-induced relapse-like drinking in rats (Kuzmin et al., 2009) i.p. No effect on ethanol consumption in DID in mice (Hendrickson et al., 2009)

α-Conotoxin PIA α6* antagonist VTA No effect on ethanol-induced locomotor stimulation or enhanced DA release in mice (Jerlhag et al., 2006)

(Continued)

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Table 1 | Continued

Drug nAChR subtype target Route of delivery Effect on ethanol behavior (in rodents)

CP-601932 α3β4 and α4β2 high affinity s.c. Decreased ethanol consumption and operant self-administration in rats partial agonist (Chatterjee et al., 2011)

PF-4575180 α3β4 high affinity partial s.c. Decreased ethanol consumption and operant self-administration in rats agonist (Chatterjee et al., 2011)

Lobeline Non-selective antagonist, s.c. Reduced ethanol consumption in DID and during continuous ethanol particularly at β2* nAChRs access in mice (Farook et al., 2009b; Sajja and Rahman, 2011) s.c. Reduced ethanol-induced DA and its metabolite levels in ventral striatum in mice (Sajja et al., 2010)

Cytisine Low-efficacy partial agonist s.c. Reduced ethanol consumption in DID in mice and during continuous with high affinity for α4β2* ethanol access in mice (Hendrickson et al., 2009; Sajja and Rahman, 2011) nAChRs. Full agonist at β4* s.c. Reduced ethanol-induced DA and its metabolite in mice (Sajja et al., 2010) and α7* nAChRs

Sazetidine-A Highly selective α4β2 s.c. Reduces alcohol intake in rats (Rezvani et al., 2010) desensitizer et al., 2003; Moroni et al., 2006; Lof et al., 2007; Kamens and NEURONAL nAChRs AND ALCOHOL: IDENTIFYING RELEVANT Phillips, 2008). The α7 selective antagonist, methyllycaconitine SUBTYPES: MOUSE GENETICS (MLA),does not affect ethanol-mediated behaviors including con- Behavioral studies in genetically engineered mice have also been sumption,ethanol-induced DA release in NAc and ethanol operant used to glean information on nAChR subtypes that may be responding in rats, as well as, consumption in mice. While caution involved in alcohol consumption and reward. Mice that do not with interpretation of these results is warranted due to data indi- express chrnb2, the gene encoding the nAChR β2 subunit (β2 KO) cating higher concentrations of MLA may also antagonize non-α7 consume and prefer ethanol in a 24 h access two-bottle choice nAChRs (of an unknown nAChR subtype that may include α6 paradigm similar to wild-type (WT) littermates indicating that and/or α3 subunits (Mogg et al., 2002)), homomeric α7 nAChRs β2∗ nAChR may not play a role in baseline ethanol consumption may not be involved in ethanol reinforcement (Larsson et al., 2002; in this assay (Kamens et al., 2010). Similarly, α6 KO and β3 KO Hendrickson et al., 2009; Kuzmin et al., 2009). On the other hand, mice consume ethanol similar to WT in a 24 h access two-bottle the α3β2∗, β3∗, and α6∗ subtype-selective antagonist, α-conotoxin choice consumption assay (Kamens et al., 2012). Female α7 KO MII (Cartier et al., 1996), when infused into the VTA does inhibit mice consume significantly less ethanol in this paradigm com- ethanol consumption, operant responding, and DA release in the pared to female WT littermates; whereas male α7 KO and WT NAc of rats (Larsson et al., 2004, 2005; Kuzmin et al., 2009) and mice consume similar amounts of ethanol indicating a potential reduce ethanol-induced locomotor stimulation and increases in gender effect of α7 nAChRs on ethanol consumption (Kamens NAc DA release in mice (Larsson et al., 2004; Jerlhag et al., 2006). et al., 2010). α5 KO mice do not differ in acute ethanol consump- Importantly, recent data indicate that approximately half of α- tion, as measured by the DID assay, compared to WT (Santos et al., conotoxin MII-sensitive nAChRs in the striatum also contain the 2012). Together, these data indicate that nAChRs containing α5, α4 subunit (Grady et al., 2007; Salminen et al., 2007) and deletion α6, β2, or β3 subunits may not be critical for ethanol consumption of β2∗ nAChRs nearly abolishes α-conotoxin MII binding in the per se. However, as nAChRs are robustly expressed in a variety of VTA (Marubio et al.,2003). However,infusion of α-conotoxin PIA, brain regions, subunit compensation may occur in a KO mouse which may have more selectivity for α6∗ nAChRs than α3∗ nAChRs background (Drago et al., 2003). Thus, these results will need to be (Dowell et al., 2003), failed to reduce ethanol-induced DA release verified using shRNAs to knock-down nAChR subunits in discreet in NAc when infused in the VTA suggesting that α3∗ nAChRs may brain regions. Interestingly, sleep time elicited by high doses of be more critical for ethanol reward. Finally, systemic injection of ethanol is increased in α6 and α5, but not β3 KO mice compared the α3β4∗ nAChR-selective antagonist 18-methoxycoranaridine to their WT littermates indicating a role for α6∗ and α5∗ nAChR in (18-MC) reduces ethanol consumption in alcohol-preferring rats alcohol-induced sedation (Kamens et al., 2012; Santos et al., 2012). (Rezvani et al., 1997). However, direct infusion of 18-MC into In contrast to the majority of KO models discussed above, acute the VTA fails to reduce alcohol consumption (Carnicella et al., ethanol consumption in the DID paradigm is significantly less in 2010) in rats consistent with data indicating low expression of β4∗ α4 KO mice compared toWT for high (20%) but not low (2%) con- nAChRs in VTA DAergic neurons (Gotti et al., 2010; Zhao-Shea centrations of ethanol implicating a role for α4∗ nAChR in ethanol et al., 2011). consumption (Hendrickson et al., 2010, 2011). In addition, the

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ability of ethanol to condition a place preference in α4 KO mice is depression by nicotine could potentially confound the interpre- reduced compared to WT. Conversely, in mice harboring a point tation of decreased ethanol self-administration, this is unlikely as mutation in α4∗ nAChRs that renders receptors hypersensitive nicotine injections did not decrease sucrose self-administration. to agonist [the Leu90Ala α4 knock-in line (Tapper et al., 2004; Thus, Sharpe and Samson(2002) propose that nicotine could be Fonck et al., 2005)], a sub-threshold dose of ethanol is sufficient acting as a reinforcer of ethanol, decreasing the amount of ethanol to condition a place preference indicating that α4∗ nAChRs mod- necessary to achieve satiety. This is in agreement with other stud- ulate alcohol reward (Liu et al., 2013). Consistent with behavioral ies in which nicotine is administered either immediately prior to, data, ethanol activation of VTA DAergic neurons is reduced in or within 30 min of, ethanol presentation or self-administration α4 KO midbrain slices and more robust in Leu90Ala midbrain (Nadal et al., 1998; Damaj, 2001). slices. Finally, ethanol potentiates the response to bath applied Toreconcile differences in nicotine effects on ethanol consump- ACh in midbrain DAergic neurons and potentiation is abolished tion and self-administration,Hauser et al. demonstrated that acute in DAergic neurons of α4 KO mice (Liu et al., 2013). Together, nicotine administration affects ethanol seeking and relapse in a these data indicate that α4∗ nAChRs in VTA DAergic neurons may time-dependent manner. Nicotine injection immediately prior to contribute to ethanol activation of the VTA and alcohol reward an ethanol operant self-administration session in ethanol prefer- although additional experiments are needed to confirm that the ring rats elicits reduced responding for ethanol compared to a observed difference in ethanol-mediated behaviors in these mouse saline injection; whereas nicotine exposure 4 h prior will increase models are due to α4∗ nAChRs in the VTA as these receptors are responses (Hauser et al.,2012). These data indicate that acute nico- expressed throughout the CNS (Baddick and Marks, 2011). tine may initially act as a substitute for ethanol at the immediate time-point causing a reduction in craving for ethanol and, at the NICOTINE AND ALCOHOL INTERACTIONS: IN VIVO STUDIES later time-point, nicotine may lead to desensitization of nAChRs Human studies have shown that individuals dependent on alco- in the brain, enhancing ethanol seeking. hol have higher rates of nicotine dependence (Room, 2004), and As in rats, acute nicotine immediately prior to presentation of smokers tend to consume more ethanol than non-smoking alco- ethanol in the DID paradigm reduces consumption in mice (Hen- hol users (York and Hirsch, 1995). Unlike the majority of clinical drickson et al.,2009); whereas chronic nicotine treatment increases studies, nicotine administration can either increase ethanol intake consumption (Sajja and Rahman, 2012). The reduction of ethanol (Potthoff et al., 1983; Blomqvist et al., 1996; Smith et al., 1999; consumption is mediated by nAChRs containing the α4 subunit: Le et al., 2000; Clark et al., 2001; Ericson et al., 2003), or decrease nicotine fails to reduce consumption in α4 KO mice; whereas acute ethanol intake (Nadal et al., 1998; Dyr et al., 1999; Sharpe and sub-threshold nicotine doses are sufficient to reduce consumption Samson, 2002) in rats. These conflicting results have led to a com- in Leu90Ala mice (Hendrickson et al., 2011). The effect of acute plex and interesting questions: under what conditions (i.e., time nicotine activates the posterior VTA as measured by increased c- delay between nicotine and ethanol, dose of nicotine, length of Fos in mouse VTA DAergic neurons while an additional injection ethanol presentation, acute versus chronic nicotine/ethanol etc.) of ethanol does not further activate these neurons, consistent with does nicotine increase ethanol intake, and what conditions cause nicotine substituting for ethanol during this treatment schedule a decrease in ethanol intake? (Hendrickson et al., 2009). Blomqvist et al.(1996) demonstrated that daily nicotine during The mechanistic basis of chronic nicotine on ethanol con- ethanol deprivation and ethanol reinstatement increases ethanol sumption is unclear. However, nicotine potentiates the response intake and preference in rats shown to have a medium baseline to ethanol in VTA DAergic neurons (Clark and Little, 2004) and preference (25–65%) for ethanol over water. Similarly, Le et al. repeated nicotine infusion into the posterior VTA increases the (2003) demonstrated that rats increased lever presses for ethanol stimulatory effects of ethanol (Ding et al., 2012). These data during the course of daily nicotine injection paired 15 min prior indicate that chronic nicotine treatment may actually increase to an operant session. These data are in agreement with various the reinforcing/rewarding properties of alcohol. Interestingly, other experiments in which nicotine was given either constantly chronic nicotine upregulates midbrain nAChRs which may lead or repeatedly (Potthoff et al., 1983; Smith et al., 1999; Ericson to increased DAergic neuron activation by ethanol (Nashmi et al., et al., 2000; Olausson et al., 2001). In rats, nicotine can also 2007). reinstate alcohol seeking after extinction and increase ethanol self- administration when administered during an ethanol deprivation NEURONAL nAChR LIGANDS FOR REDUCING ETHANOL period (Lopez-Moreno et al., 2004). Interestingly, rats given nico- CONSUMPTION tine only during the relapse period, once self-administration has While several areas of alcoholism research exist, the end goal of resumed after a deprivation period, consume less ethanol, and the majority of research is to identify new and improved treat- rats given nicotine during both abstinence and relapse increased ment options for those suffering from alcoholism. Currently, there ethanol intake compared to control (Alen et al., 2009). are three FDA approved medications for treating alcoholism. The In contrast, Sharpe and Samson demonstrated that ethanol first, disulfiram, was approved in 1954, and is classified as an anti- intake and lever pressing during operant ethanol self- relapse medication (Christensen et al., 1991). It is an acetaldehyde administration are both decreased after a high dose of nicotine dehydrogenase inhibitor, which after drinking alcohol allows the (0.7 mg/kg, subcutaneous injection (s.c.), expressed as free base buildup of acetaldehyde in the blood, causing symptoms includ- nicotine) 30 min prior to ethanol self-administration, and with ing headache, nausea, vomiting, weakness, mental confusion, or a lower dose of nicotine (0.35 mg/kg, s.c.). While locomotor anxiety (Christensen et al., 1991). However, in recent years, many

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physicians have stopped prescribing this drug because of the severe also explain some of its effects on ethanol consumption especially symptoms it causes and the fact that if a patient wished to drink in response to high doses used to reduce ethanol preference and again, they could simply not take their medication. Naltrexone, seeking in most studies using the two-bottle choice 24 h access par- available since 1994, is a competitive opioid receptor antagonist adigm of ethanol consumption. Indeed, varenicline still reduces that works by decreasing the euphoric effects produced by alcohol. ethanol consumption in β2 and α7 KO mice (Kamens et al., 2010). It is considered to be an anti-relapsing drug because it decreases Varenicline also reduces ethanol consumption in the DID para- heavy drinking in patients with alcoholism and prevents relapse to digm in α5 KO mice (Santos et al., 2012). Thus, the mechanism heaving drinking (O’Malley et al., 1992; Volpicelli et al., 1992). The of varenicline induced reduction in ethanol consumption and the third drug, acamprosate, is a partial agonist of NMDA glutamate nAChR subtype responsible for this effect is still unclear. However, receptors and an antagonist of metabotropic glutamate receptors acutely,varenicline reduces ethanol-mediated DA release in NAc of and is thought to act as an anti-craving medication by inhibit- rats, an effect that diminishes with repeated exposure of the partial ing glutamate signaling (Mason, 2003; Mason et al., 2006). While agonist (Ericson et al., 2009), consistent with varenicline reducing European studies have reported modest benefits with acamprosate, the rewarding properties of ethanol. In contrast, a recent clinical these studies have not been reproducible in the US (Pettinati et al., study found that varenicline potentiated aversion to ethanol in 2006). social drinkers (Childs et al., 2012), suggesting the agonist may Unfortunately, while these medications have been effective for reduce consumption through an anti-reward pathway. some, only 20–30% of treated patients respond to the anti-craving In addition to varenicline, pre-clinical data are emerging and anti-relapsing compounds (Spanagel, 2009). Interestingly, regarding other nAChR ligands that may prove effective in new studies have shown that people with different genetic profiles reducing ethanol consumption. Sazetidine-A, an α4β2∗ nAChR- may drink for different reasons, and also that they may respond selective “desensitizer” and partial agonist can reduces ethanol better to one type of medication versus another. For example, consumption in rats (Rezvani et al., 2010). Lobeline, an antag- populations with a specific type of mu opioid receptor respond to onist with high affinity for α4β2∗ and α3β2∗ nAChRs reduces naltrexone better than others, and this group has been described as ethanol consumption in mice in the DID and two-bottle choice “feel good drinkers”(Oslin et al., 2006; Anton et al., 2008). Another paradigm (Farook et al., 2009b). Cytisine, a partial agonist that population of alcoholics report that they drink to relieve feelings preferentially activates high affinity β2∗ nAChRs at low doses but of stress and anxiety (Kuehn, 2009) for which new medications are also is a full β4∗ nAChR agonist at high doses also reduces ethanol currently being tested (George et al., 2008). This large variability consumption (Bell et al., 2009; Hendrickson et al., 2009; Sajja and in patient response is a driving force in identifying new molecular Rahman, 2011, 2012). Both lobeline and cytisine reduced ethanol- targets for improved pharmacotherapeutic drugs. Consequently, mediated DA release in ventral striatum of mice consistent with the main focus of alcoholism treatments has been to restore the blocking of ethanol reward/reinforcement (Sajja et al., 2010). In balance to the different biochemical pathways in the brain that are addition, lobeline and cytisine also reduce the increase in alco- disrupted during alcohol dependence. hol consumption that occurs with chronic nicotine exposure in Varenicline, an α4β2 partial agonist clinically approved as a the DID paradigm (Sajja and Rahman, 2012). Finally, novel par- smoking cessation therapeutic (Coe et al., 2005; Gonzales et al., tial agonists targeting α3β4∗ nAChRs reduce ethanol consumption 2006; Jorenby et al., 2006; Tonstad et al., 2006; Steensland et al., and seeking in rats (Chatterjee et al., 2011). 2007),can reduce ethanol intake,ethanol seeking,and cue-induced ethanol reinstatement in rats (Steensland et al., 2007; Wouda et al., NEURONAL nAChR SUBUNIT GENES AND ALCOHOL: HUMAN 2011) and ethanol consumption in mice (Hendrickson et al., 2010; GENETIC ASSOCIATION STUDIES Kamens et al., 2010; Santos et al., 2012). In addition, varenicline There is growing evidence that suggests that common genes may can also reduce the enhancing effect of chronic nicotine on ethanol influence the development of alcohol and nicotine behaviors indi- self-administration in rats (Bito-Onon et al., 2011). Coupled with vidually as well as contribute to both disorders in humans (True clinical data indicating that varenicline reduces ethanol consump- et al., 1999; Bierut et al., 2000; Madden and Heath, 2002). Using tion in heavy drinking smokers (McKee et al., 2009; Fucito et al., twin studies,it was determined that identical twins are two times as 2011; Mitchell et al., 2012), uncovering the mechanism of action likely to be dependent on alcohol and/or nicotine if the other twin of varenicline could lead to more refined nAChR partial agonists is dependent, compared to fraternal twins (Heath et al., 1997). for the treatment of alcoholism. In mice, systemic injection of Recent genome wide association studies have identified sev- lower doses of varenicline immediately prior to ethanol bottle eral polymorphisms within genetic loci that includes the nAChR presentation reduces ethanol consumption in the DID paradigm subunit genes CHRNA5/A3/B4 (which encode the nAChR α5, (Hendrickson et al., 2010). In addition, this effect of varenicline α3, β4 subunit, respectively), that are associated with nicotine is reduced in α4 KO mice and enhanced in mice that express α4∗ dependence, COPD, and lung cancer (Amos et al., 2008; Berrettini nAChR that are hypersensitive to agonist indicating that activation et al., 2008; Bierut et al., 2008; Hung et al., 2008; Saccone et al., of α4∗ nAChR may underlie varenicline effects on binge drinking. 2010). Interestingly, genetic variation in these genes has also been However, while varenicline was designed to be selective for α4β2∗ associated with age of initiation of smoking and alcohol use and nAChRs at low doses, at high concentrations, varenicline is also level of response of alcohol use (Joslyn et al., 2008; Schlaepfer a partial agonist at α6β2∗ nAChRs, a full agonist at α3β4 and α7 et al., 2008). Two SNPs associated with nicotine dependence and nAChRs, as well as at 5-HT3 receptors (Mihalak et al., 2006; Papke lung cancer have been found to also be associated with a low level et al., 2010; Lummis et al., 2011; Bordia et al., 2012), which may of response to alcohol, a phenotype considered a risk factor for

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likelihood of developing an AUD (Joslyn et al., 2008). Thus, com- to its target brain regions through a conspicuous bundle of axons mon SNPs may confer susceptibility to both nicotine dependence that make up the fasciculus retroflexus. The LH projects to the and alcoholism. In addition, genetic variation in CHRNA5, dis- rostromedial tegmental nucleus that is involved in the modulation tinct from those associated with nicotine dependence, are also of DA release from the susbstantia nigra pars compacta and VTA associated with alcohol dependence (Wang et al., 2009). The (Kaufling et al., 2009; Bromberg-Martin et al., 2010a,b; Balcita- mechanistic bases for how polymorphisms in CHRNA5/A3/B4 Pedicino et al., 2011; Hong et al., 2011; Lecca et al., 2011). The modulate nicotine and alcohol phenotypes are unclear although MH projects to the interpeduncular nucleus (IPN) which, in turn, distinct SNPs in CHRNA5 have been shown to affect α4β2 nAChR projects to the median and dorsal raphe nuclei in addition to other function in vitro and mRNA expression in human brain (Bierut brain regions (Figure 2A)(Morley, 1986). Recent data indicate et al., 2008; Wang et al., 2009). It is also unclear if genetic vari- that expression of nAChRs containing the α5 and/or β4 subunits ation in CHRNA5/A3/B4 is specific for modulation of nicotine within the MH control nicotine intake such that genetic deletion and alcohol dependence as SNPs are also associated with cocaine of α5 nAChRs increases acute intake; whereas overexpression of and opioid dependence, as well as substance use initiation (Grucza the β4 nAChR subunit reduces intake and increases sensitivity to et al., 2008; Sherva et al., 2010; Lubke et al., 2012; but see Chen nicotine’s aversive properties (Fowler et al., 2011; Frahm et al., et al., 2012). Thus, SNPs in this region may affect aspects of addic- 2011). Thus, while the mesocorticolimbic pathway confers acute tion common to all drugs of abuse, such as reward, tolerance, nicotine reward/reinforcement, the MH-IPN pathway may signal or withdrawal. Alternatively, CHRNA5/A3/B4 may play a role in nicotine aversion (but see Laviolette et al., 2008). In addition, the general risk taking behavior or impulsivity which may significantly Hb-IPN is a critical circuit for the expression of physical signs predispose one to drug addiction (Stephens et al., 2012). of nicotine withdrawal (Salas et al., 2009). Because (1) SNPs in Additional genes encoding nAChR subunits have been linked nAChR subunit genes CHRNA3/A5/B4 are associated with alco- to alcohol phenotype. SNPs in CHRNB2, have been associ- hol dependence phenotypes, (2) these genes are robustly expressed ated with the subjective responses to both alcohol and nicotine in the Hb-IPN circuitry, and (3) α3β4 ligands modulate ethanol (Ehringer et al., 2007); whereas only a modest association of alco- consumption in rodent models, future studies should explore the hol responses with CHRNA4 SNPs were reported. An additional role of MH-IPN nAChRs in ethanol consumption and withdrawal study identified a CHRNA4 SNP associated with alcoholism in a behaviors. small Korean population (Kim et al., 2004). Finally, SNPs within CHRNA6 and CHRNB3 are associated with heavy alcohol con- SUMMARY sumption (Hoft et al., 2009; Landgren et al., 2009), as well as Neuronal nAChR represent novel therapeutic targets to not only treat nicotine dependence, but also alcohol dependence. The rein- smoking behavior (Thorgeirsson et al., 2010). ∗ Together these human genetic studies indicate that heritable forcing properties of acute ethanol, are mediated, in part, by α4 polymorphisms within nAChR subunit genes may predispose dis- nAChRs, likely expressed in DAergic neurons of the mesocorticol- tinct populations to increased risk for AUDs and, perhaps nicotine imbic pathway. Ethanol potentiates the response of high affinity and alcohol co-dependence. heteromeric nAChRs to both ACh and nicotine. Thus, if ethanol increases ACh release in the VTA, DAergic neurons will be acti- FUTURE DIRECTIONS vated via nAChRs and ethanol will further potentiate this effect Emerging evidence indicates that SNPs within genes encoding (Figure 2B). Chronic nicotine may upregulate these receptors nAChR subunits are associated with alcohol dependence pheno- and increase the reinforcing properties of ethanol. Future studies types. Additional research is needed to understand how SNPs in should focus on identifying additional nAChR subunits critical for these subunits modulate the effects of ethanol on nAChRs directly ethanol effects within and outside the mesocorticolimbic circuitry. and in animal models of ethanol dependence. It will also be critical to expand the focus of nAChRs and ethanol effects on ACKNOWLEDGMENTS circuits outside of the mesocorticolimbic pathway. Indeed, recent This study was supported by the National Institute on Alcohol data indicate that nicotine intake is controlled by the habenulo- Abuse and Alcoholism award number R01AA017656 (Andrew R. peduncular axis. This circuit consists of a small, epithalamic struc- Tapper) and F31AA018915 (Linzy M. Hendrickson). The content ture, the habenula (Hb) which can be divided into medial (MH) is solely the responsibility of the authors and does not necessarily and lateral (LH) sub-regions (Hikosaka, 2010). The Hb projects represent the official views of the National Institutes of Health.

REFERENCES Alen, F., Gomez, R., Gonzalez-Cuevas, susceptibility locus for lung can- (COMBINE) study. Arch. Gen. Psy- Aistrup, G. L., Marszalec, W., and G., Navarro, M., and Lopez-Moreno, cer at 15q25.1. Nat. Genet. 40, chiatry 65, 135–144. Narahashi, T. (1999). Ethanol mod- J. A. (2009). Nicotine causes oppo- 616–622. Baddick, C. G., and Marks, M. J. ulation of nicotinic acetylcholine site effects on alcohol intake: evi- Anton, R. F., Oroszi, G., O’Malley, S., (2011). An autoradiographic sur- receptor currents in cultured cor- dence in an animal experimental Couper, D., Swift, R., Pettinati, H., vey of mouse brain nicotinic acetyl- tical neurons. Mol. Pharmacol. 55, model of abstinence and relapse et al. (2008). An evaluation of mu- choline receptors defined by null 39–49. from alcohol. Nicotine Tob. Res. 11, opioid receptor (OPRM1) as a pre- mutants. Biochem. Pharmacol. 82, Albuquerque, E. X., Pereira, E. F.,Alkon- 1304–1311. dictor of naltrexone response in the 828–841. don, M., and Rogers, S. W. (2009). Amos, C. I., Wu, X., Broderick, P. treatment of alcohol dependence: Balcita-Pedicino, J. J., Omelchenko, Mammalian nicotinic acetylcholine I., Gorlov, P., Gu, J., Eisen, T., et results from the combined phar- N., Bell, R., and Sesack, S. R. receptors: from structure to func- al. (2008). Genome-wide associa- macotherapies and behavioral inter- (2011). The inhibitory influence of tion. Physiol. Rev. 89, 73–120. tion scan of tag SNPs identifies a ventions for alcohol dependence the lateral habenula on midbrain

Frontiers in Psychiatry | Addictive Disorders and Behavioral Dyscontrol April 2013 | Volume 4 | Article 29| 10 Hendrickson et al. Nicotinic receptors in alcohol dependence

dopamine cells: ultrastructural evi- subchronic nicotine treatment. Eur. Carnicella, S., He, D. Y., Yowell, Q. Chi,H.,and de Wit,H. (2003). Mecamy- dence for indirect mediation via the J. Pharmacol. 314, 257–267. V., Glick, S. D., and Ron, D. lamine attenuates the subjective rostromedial mesopontine tegmen- Blomqvist,O.,Soderpalm,B.,and Engel, (2010). Noribogaine, but not 18- stimulant-like effects of alcohol in tal nucleus. J. Comp. Neurol. 519, J. A. (1992). Ethanol-induced loco- MC, exhibits similar actions as ibo- social drinkers. Alcohol. Clin. Exp. 1143–1164. motor activity: involvement of cen- gaine on GDNF expression and Res. 27, 780–786. Bell, R. L., Eiler, B. J. II, Cook, J. B., and tral nicotinic acetylcholine recep- ethanol self-administration. Addict. Childs, E., Roche, D. J., King, A. C., Rahman, S. (2009). Nicotinic recep- tors? Brain Res. Bull. 29, 173–178. Biol. 15, 424–433. and de Wit, H. (2012). Varenicline tor ligands reduce ethanol intake by Bobo, J. K. (1992). Nicotine dependence Carr, D. B., and Sesack, S. R. (2000). potentiates alcohol-induced nega- high alcohol-drinking HAD-2 rats. and alcoholism epidemiology and GABA-containing neurons in the rat tive subjective responses and offsets Alcohol 43, 581–592. treatment. J. Psychoactive Drugs 24, ventral tegmental area project to impaired eye movements. Alcohol. Benwell, M. E., and Balfour, D. J. 123–129. the prefrontal cortex. Synapse 38, Clin. Exp. Res. 36, 906–914. (1992). The effects of acute and Bobo, J. K., and Husten, C. (2000). 114–123. Christensen, J. K., Moller, I. W., Ron- repeated nicotine treatment on Sociocultural influences on smoking Cartier, G. E., Yoshikami, D., Gray, W. sted, P., and Johansson, B. (1991). nucleus accumbens dopamine and and drinking. Alcohol Res. Health 24, R., Luo, S., Olivera, B. M., and McIn- Dose-effect relationship of disulfi- locomotor activity. Br. J. Pharmacol. 225–232. tosh, J. M. (1996). A new alpha- ram in human volunteers. I: clini- 105, 849–856. Bordia, T., Hrachova, M., Chin, M., conotoxin which targets alpha3beta2 cal studies. Pharmacol. Toxicol. 68, Berrettini, W., Yuan, X., Tozzi, F., Song, McIntosh, J. M., and Quik, M. nicotinic acetylcholine receptors. J. 163–165. K., Francks, C., Chilcoat, H., et (2012). Varenicline is a potent par- Biol. Chem. 271, 7522–7528. Clark, A., Lindgren, S., Brooks, S. P., al. (2008). Alpha-5/alpha-3 nicotinic tial agonist at α6β2∗ nicotinic acetyl- CASA. (2000). CASA’s cost of living Watson,W.P.,and Little,H. J. (2001). receptor subunit alleles increase risk choline receptors in rat and monkey adjustment, using the Bureau of Chronic infusion of nicotine can for heavy smoking. Mol. Psychiatry striatum. J. Pharmacol. Exp. Ther. Labor Statistics Inflation Calcula- increase operant self-administration 13, 368–373. 342, 327–334. tor, of 1998 data by Harwood, H. of alcohol. Neuropharmacology 41, Bhutada, P., Mundhada, Y., Ghodki, Borghese, C. M.,Ali, D. N., Bleck,V.,and Updating Estimates of the Economic 108–117. Y., Dixit, P., Umathe, S., and Harris, R. A. (2002). Acetylcholine Costs of Alcohol Abuse in the United Clark, A., and Little, H. J. (2004). Inter- Jain, K. (2012). Acquisition, expres- and alcohol sensitivity of neu- States: Estimates, Update Methods, actions between low concentrations sion, and reinstatement of ethanol- ronal nicotinic acetylcholine recep- and Data. Report prepared by The of ethanol and nicotine on firing induced conditioned place prefer- tors: mutations in transmembrane Lewin Group for the National Insti- rate of ventral tegmental dopamine ence in mice: effects of exposure to domains. Alcohol. Clin. Exp. Res. 26, tute on Alcohol Abuse and Alco- neurones. Drug Alcohol Depend. 75, stress and modulation by mecamy- 1764–1772. holism, 2000. Based on estimates, 199–206. lamine. J. Psychopharmacol. 26, Borghese, C. M., Henderson, L. A., analyses, and data reported in Har- Coe, J. W., Brooks, P. R., Vetelino, M. G., 315–323. Bleck, V., Trudell, J. R., and Har- wood, H., Fountain, D., and Liver- Wirtz, M. C., Arnold, E. P., Huang, Bierut, L. J., Schuckit, M. A., Hessel- ris, R. A. (2003a). Sites of excitatory more, G. (1992). The Economic Costs J., et al. (2005). Varenicline: an brock, V., and Reich, T. (2000). Co- and inhibitory actions of alcohols of Alcohol and Drug Abuse in the alpha4beta2 nicotinic receptor par- occurring risk factors for alcohol on neuronal alpha2beta4 nicotinic United States. Report prepared for tial agonist for smoking cessation. J. dependence and habitual smoking. acetylcholine receptors. J. Pharma- the National Institute on DrugAbuse Med. Chem. 48, 3474–3477. Alcohol Res. Health 24, 233–241. col. Exp. Ther. 307, 42–52. and the National Institute on Alco- Cornwall, J., Cooper, J. D., and Phillip- Bierut, L. J., Stitzel, J. A., Wang, J. C., Borghese, C. M., Wang, L., Bleck, V., hol Abuse and Alcoholism National son, O. T. (1990). Afferent and effer- Hinrichs, A. L., Grucza, R. A., Xuei, and Harris, R. A. (2003b). Muta- Institutes of Health, U.S. Depart- ent connections of the laterodorsal X., et al. (2008). Variants in nico- tion in neuronal nicotinic acetyl- ment of Health and Human Ser- tegmental nucleus in the rat. Brain tinic receptors and risk for nicotine choline receptors expressed in Xeno- vices. NIH Publication No 98-4327. Res. Bull. 25, 271–284. dependence. Am. J. Psychiatry 165, pus oocytes blocks ethanol action. Rockville, MD. (2005). Corrigall,W.A.,and Coen,K. M. (1991). 1163–1171. Addict. Biol. 8, 313–318. Champtiaux, N., Han, Z. Y., Bessis, A., Selective dopamine antagonists Bito-Onon, J. J., Simms, J. A., Chat- Bromberg-Martin, E. S., Matsumoto, Rossi, F. M., Zoli, M., Marubio, L., et reduce nicotine self-administration. terjee, S., Holgate, J., and Bartlett, M., Nakahara, H., and Hikosaka, al. (2002). Distribution and pharma- Psychopharmacology (Berl.) 104, S. E. (2011). Varenicline, a par- O. (2010a). Multiple timescales of cology of alpha 6-containing nico- 171–176. tial agonist at neuronal nico- memory in lateral habenula and tinic acetylcholine receptors ana- Corrigall, W. A., Coen, K. M., and tinic acetylcholine receptors,reduces dopamine neurons. Neuron 67, lyzed with mutant mice. J. Neurosci. Adamson, K. L. (1994). Self- nicotine-induced increases in 20% 499–510. 22, 1208–1217. administered nicotine activates ethanol operant self-administration Bromberg-Martin, E. S., Matsumoto, Changeux, J. P., and Edelstein, S. J. the mesolimbic dopamine system in Sprague-Dawley rats. Addict. Biol. M., and Hikosaka, O. (2010b). Dis- (1998). Allosteric receptors after 30 through the ventral tegmental area. 16, 440–449. tinct tonic and phasic anticipa- years. Neuron 21, 959–980. Brain Res. 653, 278–284. Blomqvist, O., Engel, J. A., Niss- tory activity in lateral habenula Chatterjee, S., Steensland, P., Simms, J. Corrigall, W. A., Franklin, K. B., Coen, brandt, H., and Soderpalm, B. and dopamine neurons. Neuron 67, A., Holgate, J., Coe, J. W., Hurst, K. M., and Clarke, P. B. (1992). (1993). The mesolimbic dopamine- 144–155. R. S., et al. (2011). Partial agonists The mesolimbic dopaminergic sys- activating properties of ethanol are Buisson, B., and Bertrand, D. (2001). of the alpha3beta4∗ neuronal nico- tem is implicated in the reinforcing antagonized by mecamylamine. Eur. Chronic exposure to nicotine upreg- tinic acetylcholine receptor reduce effects of nicotine. Psychopharmacol- J. Pharmacol. 249, 207–213. ulates the human (alpha)4((beta)2 ethanol consumption and seeking in ogy (Berl.) 107, 285–259. Blomqvist, O., Ericson, M., Engel, nicotinic acetylcholine recep- rats. Neuropsychopharmacology 36, Corringer, P. J., Le Novere, N., and J. A., and Soderpalm, B. (1997). tor function. J. Neurosci. 21, 603–615. Changeux, J. P. (2000). Nicotinic Accumbal dopamine overflow after 1819–1829. Chen, L. S., Xian, H., Grucza, R. A., Sac- receptors at the amino acid level. ethanol: localization of the antago- Cardoso, R. A., Brozowski, S. J., Chavez- cone, N. L., Wang, J. C., Johnson, Annu. Rev. Pharmacol. Toxicol. 40, nizing effect of mecamylamine. Eur. Noriega, L. E., Harpold, M., Valen- E. O., et al. (2012). Nicotine depen- 431–458. J. Pharmacol. 334, 149–156. zuela, C. F., and Harris, R. A. (1999). dence and comorbid psychiatric Damaj,M. I. (2001). Influence of gender Blomqvist, O., Ericson, M., Johnson, Effects of ethanol on recombinant disorders: examination of specific and sex hormones on nicotine acute D. H., Engel, J. A., and Soder- human neuronal nicotinic acetyl- genetic variants in the CHRNA5- pharmacological effects in mice. J. palm, B. (1996). Voluntary ethanol choline receptors expressed in Xeno- A3-B4 nicotinic receptor genes. Pharmacol. Exp. Ther. 296, 132–140. intake in the rat: effects of nicotinic pus oocytes. J. Pharmacol. Exp. Ther. Drug Alcohol Depend. 123(Suppl. 1), Dani, J. A., and Bertrand, D. (2007). acetylcholine receptor blockade or 289, 774–780. S42–51. Nicotinic acetylcholine receptors

www.frontiersin.org April 2013 | Volume 4 | Article 29| 11 Hendrickson et al. Nicotinic receptors in alcohol dependence

and nicotinic cholinergic mecha- tegmental mecamylamine. Eur. J. Forman, S. A., and Zhou, Q. (1999). on dopamine release, locomotion, nisms of the central nervous system. Pharmacol. 358, 189–196. Novel modulation of a nicotinic and reinforcement. J. Neurosci. 30, Annu. Rev. Pharmacol. Toxicol. 47, Ericson, M., Engel, J. A., and Soderpalm, receptor channel mutant reveals 5311–5325. 699–729. B. (2000). Peripheral involvement that the open state is stabilized Gotti, C., Moretti, M., Gaimarri, A., De Biasi, M., and Dani, J. A. (2011). in nicotine-induced enhancement of by ethanol. Mol. Pharmacol. 55, Zanardi, A., Clementi, F., and Zoli, Reward, addiction, withdrawal to ethanol intake. Alcohol 21, 37–47. 102–108. M. (2007). Heterogeneity and com- nicotine. Annu. Rev. Neurosci. 34, Ericson, M., Lof, E., Stomberg, R., and Fowler, C. D., Lu, Q., Johnson, P. M., plexity of native brain nicotinic 105–130. Soderpalm, B. (2009). The smok- Marks, M. J., and Kenny, P. J. (2011). receptors. Biochem. Pharmacol. 74, Di Chiara, G., and Imperato, A. (1988). ing cessation medication vareni- Habenular alpha5 nicotinic receptor 1102–1111. Drugs abused by humans prefer- cline attenuates alcohol and nicotine subunit signalling controls nicotine Grady, S. R., Salminen, O., Laverty, D. entially increase synaptic dopamine interactions in the rat mesolimbic intake. Nature 471, 597–601. C., Whiteaker, P., McIntosh, J. M., concentrations in the mesolim- dopamine system. J. Pharmacol. Exp. Frahm, S., Slimak, M. A., Ferrarese, L., Collins, A. C., et al. (2007). The bic system of freely moving rats. Ther. 329, 225–230. Santos-Torres, J., Antolin-Fontes, B., subtypes of nicotinic acetylcholine Proc. Natl. Acad. Sci. U.S.A. 85, Ericson, M., Molander, A., Lof, E., Auer, S., et al. (2011). Aversion to receptors on dopaminergic termi- 5274–5278. Engel, J. A., and Soderpalm, B. nicotine is regulated by the balanced nals of mouse striatum. Biochem. Diana, M., Rossetti, Z. L., and Gessa, (2003). Ethanol elevates accum- activity of beta4 and alpha5 nico- Pharmacol. 74, 1235–1246. G. (1993). Rewarding and aver- bal dopamine levels via indirect tinic receptor subunits in the medial Grant, B. F., Hasin, D. S., Chou, sive effects of ethanol: interplay of activation of ventral tegmental habenula. Neuron 70, 522–535. S. P., Stinson, F. S., and Daw- GABA, glutamate and dopamine. nicotinic acetylcholine recep- Fucito, L. M., Toll, B. A., Wu, R., son, D. A. (2004). Nicotine depen- Alcohol. Alcohol Suppl. 2, 315–319. tors. Eur. J. Pharmacol. 467, Romano, D. M., Tek, E., and dence and psychiatric disorders in DiFranza, J. R., and Guerrera, M. P. 85–93. O’Malley, S. S. (2011). A pre- the United States: results from (1990). Alcoholism and smoking. J. Exley, R., Maubourguet, N., David, V., liminary investigation of vareni- the national epidemiologic sur- Stud. Alcohol 51, 130–135. Eddine, R., Evrard, A., Pons, S., et cline for heavy drinking smok- vey on alcohol and related con- Ding, Z. M., Katner, S. N., Rodd, Z. A., al. (2011). Distinct contributions of ers. Psychopharmacology (Berl.) 215, ditions. Arch. Gen. Psychiatry 61, Truitt, W., Hauser, S. R., Deehan, G. nicotinic acetylcholine receptor sub- 655–663. 1107–1115. A. Jr., et al. (2012). Repeated expo- unit alpha4 and subunit alpha6 to Funk, D., Marinelli, P. W., and Le, A. D. Grucza, R. A., Wang, J. C., Stitzel, J. sure of the posterior ventral tegmen- the reinforcing effects of nicotine. (2006). Biological processes under- A., Hinrichs, A. L., Saccone, S. F., tal area to nicotine increases the sen- Proc. Natl. Acad. Sci. U.S.A. 108, lying co-use of alcohol and nico- Saccone, N. L., et al. (2008). A risk sitivity of local dopamine neurons 7577–7582. tine: neuronal mechanisms, cross- allele for nicotine dependence in to the stimulating effects of ethanol. Fallon, J. H., Schmued, L. C., Wang, C., tolerance, and genetic factors. Alco- CHRNA5 is a protective allele for Alcohol 46, 217–223. Miller, R., and Banales, G. (1984). hol Res. Health 29, 186–192. cocaine dependence. Biol. Psychiatry Dopico, A. M., and Lovinger, D. Neurons in the ventral tegmentum Gatto, G. J., McBride, W. J., Murphy, J. 64, 922–929. M. (2009). Acute alcohol action have separate populations project- M., Lumeng, L., and Li, T. K. (1994). Guan, Y., Xiao, C., Krnjevic, K., Xie, and desensitization of ligand-gated ing to telencephalon and inferior Ethanol self-infusion into the ventral G., Zuo, W., and Ye, J. H. (2012). ion channels. Pharmacol. Rev. 61, olive, are histochemically different, tegmental area by alcohol-preferring GABAergic actions mediate oppo- 98–114. and may receive direct visual input. rats. Alcohol 11, 557–564. site ethanol effects on dopaminergic Dowell, C., Olivera, B. M., Garrett, Brain Res. 321, 332–336. Geisler, S., and Zahm, D. S. (2005). neurons in the anterior and poste- J. E., Staheli, S. T., Watkins, M., Farook,J. M.,Lewis,B.,Gaddis,J. G.,Lit- Afferents of the ventral tegmen- rior ventral tegmental area. J. Phar- Kuryatov, A., et al. (2003). Alpha- tleton, J. M., and Barron, S. (2009a). tal area in the rat-anatomical sub- macol. Exp. Ther. 341, 33–42. conotoxin PIA is selective for alpha6 Effects of mecamylamine on alco- stratum for integrative functions. J. Harvey, S. C., and Luetje, C. W. (1996). subunit-containing nicotinic acetyl- hol consumption and preference in Comp. Neurol. 490, 270–294. Determinants of competitive antag- choline receptors. J. Neurosci. 23, male C57BL/6J mice. Pharmacology George, D. T., Gilman, J., Hersh, J., onist sensitivity on neuronal nico- 8445–8452. 83, 379–384. Thorsell, A., Herion, D., Geyer, C., tinic receptor beta subunits. J. Neu- Drago, J., McColl, C. D., Horne, M. Farook,J. M.,Lewis,B.,Gaddis,J. G.,Lit- et al. (2008). Neurokinin 1 receptor rosci. 16, 3798–3806. K., Finkelstein, D. I., and Ross, tleton, J. M., and Barron, S. (2009b). antagonism as a possible therapy for Harvey, S. C., Maddox, F. N., and Luetje, S. A. (2003). Neuronal nicotinic Lobeline, a nicotinic partial agonist alcoholism. Science 319, 1536–1539. C. W. (1996). Multiple determi- receptors: insights gained from gene attenuates alcohol consumption and Gessa, G. L., Muntoni, F., Collu, nants of dihydro-beta-erythroidine knockout and knockin mutant mice. preference in male C57BL/6J mice. M., Vargiu, L., and Mereu, G. sensitivity on rat neuronal nico- Cell. Mol. Life Sci. 60, 1267–1280. Physiol. Behav. 97, 503–506. (1985). Low doses of ethanol activate tinic receptor alpha subunits. J. Neu- Dyr, W., Koros, E., Bienkowski, P., and Fields, H. L., Hjelmstad, G. O., Margo- dopaminergic neurons in the ven- rochem. 67, 1953–1959. Kostowski, W. (1999). Involvement lis, E. B., and Nicola, S. M. (2007). tral tegmental area. Brain Res. 348, Hauser, S. R., Getachew, B., Oster, S. of nicotinic acetylcholine receptors Ventral tegmental area neurons in 201–203. M., Dhaher, R., Ding, Z. M., Bell, in the regulation of alcohol drink- learned appetitive behavior and pos- Gonzales, D., Rennard, S. I., Nides, R. L., et al. (2012). Nicotine modu- ing in Wistar rats. Alcohol Alcohol. itive reinforcement. Annu. Rev. Neu- M., Oncken, C., Azoulay, S., Billing, lates alcohol-seeking and relapse by 34, 43–47. rosci. 30, 289–316. C. B., et al. (2006). Varenicline, alcohol-preferring (P) rats in a time- Ehringer, M. A., Clegg, H. V.,Collins, A. Foddai, M., Dosia, G., Spiga, S., an alpha4beta2 nicotinic acetyl- dependent manner. Alcohol. Clin. C., Corley, R. P., Crowley, T., Hewitt, and Diana, M. (2004). Acetalde- choline receptor partial agonist, Exp. Res. 36, 43–54. J. K., et al. (2007). Association of the hyde increases dopaminergic neu- vs sustained-release bupropion and Heath, A. C., Bucholz, K. K., Mad- neuronal nicotinic receptor beta2 ronal activity in the VTA. Neuropsy- placebo for smoking cessation: a den, P. A., Dinwiddie, S. H., Slutske, subunit gene (CHRNB2) with sub- chopharmacology 29, 530–536. randomized controlled trial. JAMA W. S., Bierut, L. J., et al. (1997). jective responses to alcohol and Fonck, C., Cohen, B. N., Nashmi, 296, 47–55. Genetic and environmental contri- nicotine. Am. J. Med. Genet. B Neu- R., Whiteaker, P., Wagenaar, D. Gotti, C., Guiducci, S., Tedesco, V., Cor- butions to alcohol dependence risk ropsychiatr. Genet. 144B, 596–604. A., Rodrigues-Pinguet, N., et al. bioli, S., Zanetti, L., Moretti, M., et in a national twin sample: consis- Ericson, M., Blomqvist, O., Engel, J. A., (2005). Novel seizure phenotype al. (2010). Nicotinic acetylcholine tency of findings in women and men. and Soderpalm, B. (1998). Volun- and sleep disruptions in knock-in receptors in the mesolimbic path- Psychol. Med. 27, 1381–1396. tary ethanol intake in the rat and mice with hypersensitive alpha 4∗ way: primary role of ventral tegmen- Hendrickson, L. M., Gardner, P., and the associated accumbal dopamine nicotinic receptors. J. Neurosci. 25, tal area alpha6beta2∗ receptors in Tapper, A. R. (2011). Nicotinic overflow are blocked by ventral 11396–11411. mediating systemic nicotine effects acetylcholine receptors containing

Frontiers in Psychiatry | Addictive Disorders and Behavioral Dyscontrol April 2013 | Volume 4 | Article 29| 12 Hendrickson et al. Nicotinic receptors in alcohol dependence

the alpha4 subunit are critical for Jerlhag, E., Grotli, M., Luthman, K., Kaufling, J., Veinante, P., Pawlowski, (2004). Is an alpha-conotoxin MII- the nicotine-induced reduction of Svensson, L., and Engel, J. A. S. A., Freund-Mercier, M. J., and sensitive mechanism involved in acute voluntary ethanol consump- (2006). Role of the subunit com- Barrot, M. (2009). Afferents to the neurochemical, stimulatory, and tion. Channels (Austin) 5, 124–127. position of central nicotinic acetyl- the GABAergic tail of the ventral rewarding effects of ethanol? Alcohol Hendrickson, L. M., Zhao-Shea, R., choline receptors for the stim- tegmental area in the rat. J. Comp. 34, 239–250. Pang, X., Gardner, P. D., and Tapper, ulatory and dopamine-enhancing Neurol. 513, 597–621. Larsson, A., Svensson, L., Soderpalm, B., A. R. (2010). Activation of alpha4∗ effects of ethanol. Alcohol Alcohol. Kiianmaa, K. (1978). Decreased and Engel,J.A. (2002). Role of differ- nAChRs is necessary and sufficient 41, 486–493. intoxicating effect of ethanol in ent nicotinic acetylcholine receptors for varenicline-induced reduction of Ji, H., and Shepard, P. D. (2007). Lat- rats after 6-hydroxydopamine- in mediating behavioral and neuro- alcohol consumption. J. Neurosci. eral habenula stimulation inhibits induced degeneration of ascending chemical effects of ethanol in mice. 30, 10169–10176. rat midbrain dopamine neurons dopamine pathways. Pharmacol. Alcohol 28, 157–167. Hendrickson, L. M., Zhao-Shea, R., through a GABA(A) receptor- Biochem. Behav. 9, 391–393. Laviolette, S. R., Lauzon, N. M., Bishop, and Tapper, A. R. (2009). Modu- mediated mechanism. J. Neurosci. Kim, S. A., Kim, J. W., Song, J. Y., S. F., Sun, N., and Tan, H. (2008). lation of ethanol drinking-in-the- 27, 6923–6930. Park, S., Lee, H. J., and Chung, Dopamine signaling through D1- dark by mecamylamine and nico- Job, M. O., Tang, A., Hall, F. S., Sora, J. H. (2004). Association of poly- like versus D2-like receptors in tinic acetylcholine receptor agonists I., Uhl, G. R., Bergeson, S. E., et morphisms in nicotinic acetyl- the nucleus accumbens core versus in C57BL/6J mice. Psychopharmacol- al. (2007). Mu (mu) opioid recep- choline receptor alpha 4 subunit shell differentially modulates nico- ogy (Berl.) 204, 563–572. tor regulation of ethanol-induced gene (CHRNA4), mu-opioid recep- tine reward sensitivity. J. Neurosci. Herkenham, M., and Nauta, W. J. dopamine response in the ventral tor gene (OPRM1), and ethanol- 28, 8025–8033. (1979). Efferent connections of the striatum: evidence of genotype spe- metabolizing enzyme genes with Le, A. D., Corrigall, W. A., Harding, J. habenular nuclei in the rat. J. Comp. cific sexual dimorphic epistasis. Biol. alcoholism in Korean patients. Alco- W.,Juzytsch,W.,and Li, T. K. (2000). Neurol. 187, 19–47. Psychiatry 62, 627–634. hol 34, 115–120. Involvement of nicotinic receptors Hikosaka, O. (2010). The habenula: Johnson, D. H., Blomqvist, O., Engel, Klink, R., de Kerchove d’Exaerde, A., in alcohol self-administration. from stress evasion to value-based J. A., and Soderpalm, B. (1995). Zoli, M., and Changeux, J. P. (2001). Alcohol. Clin. Exp. Res. 24, decision-making. Nat. Rev. Neurosci. Subchronic intermittent nicotine Molecular and physiological diver- 155–163. 11, 503–513. treatment enhances ethanol- sity of nicotinic acetylcholine recep- Le, A. D., Wang, A., Harding, S., Hoft, N. R., Corley, R. P., McQueen, induced locomotor stimulation and tors in the midbrain dopaminergic Juzytsch, W., and Shaham, Y. (2003). M. B., Huizinga, D., Menard, S., and dopamine turnover in mice. Behav. nuclei. J. Neurosci. 21, 1452–1463. Nicotine increases alcohol self- Ehringer, M. A. (2009). SNPs in Pharmacol. 6, 203–207. Koob, G. F. (1992). Drugs of abuse: administration and reinstates alco- CHRNA6 and CHRNB3 are associ- Jorenby, D. E., Hays, J. T., Rigotti, N. A., anatomy, pharmacology and func- hol seeking in rats. Psychopharma- ated with alcohol consumption in Azoulay, S., Watsky, E. J., Williams, tion of reward pathways. Trends cology (Berl.) 168, 216–221. a nationally representative sample. K. E., et al. (2006). Efficacy of Pharmacol. Sci. 13, 177–184. Le Novere, N., and Changeux, J. P. Genes Brain Behav. 8, 631–637. varenicline,an alpha4beta2 nicotinic Koob, G. F., and Weiss, F. (1990). (1995). Molecular evolution of the Hong, S., Jhou, T. C., Smith, M., Saleem, acetylcholine receptor partial ago- Pharmacology of drug self- nicotinic acetylcholine receptor: an K. S., and Hikosaka, O. (2011). Neg- nist, vs placebo or sustained-release administration. Alcohol 7, example of multigene family in ative reward signals from the lateral bupropion for smoking cessation: a 193–197. excitable cells. J. Mol. Evol. 40, habenula to dopamine neurons are randomized controlled trial. JAMA Kuehn, B. M. (2009). Findings on alco- 155–172. mediated by rostromedial tegmental 296, 56–63. hol dependence point to promis- Lecca,S.,Melis,M.,Luchicchi,A.,Ennas, nucleus in primates. J. Neurosci. 31, Joslyn, G., Brush, G., Robertson, M., ing avenues for targeted therapies. M. G., Castelli, M. P., Muntoni, A. 11457–11471. Smith,T.L.,Kalmijn,J.,Schuckit,M., JAMA 301, 1643–1645. L., et al. (2011). Effects of drugs Hung, R. J., McKay, J. D., Gaborieau, et al. (2008). Chromosome 15q25.1 Kuzmin, A., Jerlhag, E., Liljequist, S., of abuse on putative rostrome- V., Boffetta, P.,Hashibe, M., Zaridze, genetic markers associated with level and Engel, J. (2009). Effects of dial tegmental neurons, inhibitory D., et al. (2008). A susceptibil- of response to alcohol in humans. subunit selective nACh receptors on afferents to midbrain dopamine ity locus for lung cancer maps to Proc. Natl. Acad. Sci. U.S.A. 105, operant ethanol self-administration cells. Neuropsychopharmacology 36, nicotinic acetylcholine receptor sub- 20368–20373. and relapse-like ethanol-drinking 589–602. unit genes on 15q25. Nature 452, Kamens, H. M., Andersen, J., and Pic- behavior. Psychopharmacology Lewis, M. J., and June, H. L. (1990). 633–637. ciotto, M. R. (2010). Modulation (Berl.) 203, 99–108. Neurobehavioral studies of ethanol Ikemoto, S. (2007). Dopamine reward of ethanol consumption by genetic Lanca, A. J. (1994). Reduction of vol- reward and activation. Alcohol 7, circuitry: two projection systems and pharmacological manipulation untary alcohol intake in the rat 213–219. from the ventral midbrain to the of nicotinic acetylcholine recep- by modulation of the dopamin- Li, W., Doyon, W. M., and Dani, J. nucleus accumbens-olfactory tuber- tors in mice. Psychopharmacology ergic mesolimbic system: trans- A. (2011). Acute in vivo nicotine cle complex. Brain Res. Rev. 56, (Berl.) 208, 613–626. plantation of ventral mesencephalic administration enhances synchrony 27–78. Kamens, H. M., Hoft, N. R., Cox, R. J., cell suspensions. Neuroscience 58, among dopamine neurons. Biochem. Ikemoto, S., McBride, W. J., Mur- Miyamoto, J. H., and Ehringer, M. A. 359–369. Pharmacol. 82, 977–983. phy, J. M., Lumeng, L., and Li, (2012). The alpha6 nicotinic acetyl- Landgren, S., Engel, J. A., Andersson, M. Littleton, J., Barron, S., Prendergast, M., T. K. (1997). 6-OHDA-lesions of choline receptor subunit influences E., Gonzalez-Quintela, A., Campos, and Nixon,S. J. (2007). Smoking kills the nucleus accumbens disrupt the ethanol-induced sedation. Alcohol J., Nilsson, S., et al. (2009). Associa- (alcoholics)! shouldn’t we do some- acquisition but not the mainte- 46, 463–471. tion of nAChR gene haplotypes with thing about it? Alcohol Alcohol. 42, nance of ethanol consumption in Kamens, H. M., and Phillips, T. heavy alcohol use and body mass. 167–173. the alcohol-preferring P line of J. (2008). A role for neuronal Brain Res. 1305(Suppl.), S72–9. Liu, L., Hendrickson, L. M., Guild- rats. Alcohol. Clin. Exp. Res. 21, nicotinic acetylcholine receptors in Larsson, A., Edstrom, L., Svensson, L., ford, M., Zhao-Shea, R., Gardner, P. 1042–1046. ethanol-induced stimulation, but Soderpalm, B., and Engel, J. A. D., and Tapper, A. R. (2013). Nico- Ikemoto, S., Qin, M., and Liu, Z. H. not cocaine- or methamphetamine- (2005). Voluntary ethanol intake tinic acetylcholine receptors con- (2006). Primary reinforcing effects induced stimulation. Psychophar- increases extracellular acetylcholine taining the alpha4 subunit modulate of nicotine are triggered from mul- macology (Berl.) 196, 377–387. levels in the ventral tegmental area in alcohol reward. Biol. Psychiatry. 73, tiple regions both inside and out- Karlin,A. (2002). Emerging structure of the rat. Alcohol Alcohol. 40, 349–358. 738–746. side the ventral tegmental area. J. the nicotinic acetylcholine receptors. Larsson, A., Jerlhag, E., Svensson, L., Liu, L., Zhao-Shea, R., McIntosh, J. Neurosci. 26, 723–730. Nat. Rev. Neurosci. 3, 102–114. Soderpalm, B., and Engel, J. A. M., Gardner, P. D., and Tapper,

www.frontiersin.org April 2013 | Volume 4 | Article 29| 13 Hendrickson et al. Nicotinic receptors in alcohol dependence

A. R. (2012). Nicotine persistently Marubio, L. M., Gardier, A. M., Millar, N. S., and Gotti, C. (2009). (2003). Alternate stoichiometries of activates ventral tegmental area Durier, S., David, D., Klink, R., Diversity of vertebrate nicotinic alpha4beta2 nicotinic acetylcholine dopaminergic neurons via nicotinic Arroyo-Jimenez,M. M.,et al. (2003). acetylcholine receptors. Neurophar- receptors. Mol. Pharmacol. 63, acetylcholine receptors containing Effects of nicotine in the dopaminer- macology 56, 237–246. 332–341. alpha4 and alpha6 subunits. Mol. gic system of mice lacking the alpha4 Miller, N. S., and Gold, M. S. (1998). Oakman, S. A., Faris, P. L., Kerr, P. Pharmacol. 81, 541–548. subunit of neuronal nicotinic acetyl- Comorbid cigarette and alcohol E., Cozzari, C., and Hartman, B. K. Lof, E., Olausson, P., deBejczy, A., choline receptors. Eur. J. Neurosci. addiction: epidemiology and treat- (1995). Distribution of pontomes- Stomberg, R., McIntosh, J. M., Tay- 17, 1329–1337. ment. J. Addict. Dis. 17, 55–66. encephalic cholinergic neurons pro- lor, J. R., et al. (2007). Nico- Maskos, U., Molles, B. E., Pons, S., Mitchell, J. M., Teague, C. H., Kayser, jecting to substantia nigra differs sig- tinic acetylcholine receptors in Besson, M., Guiard, B. P., Guilloux, A. S., Bartlett, S. E., and Fields, nificantly from those projecting to the ventral tegmental area medi- J. P., et al. (2005). Nicotine rein- H. L. (2012). Varenicline decreases ventral tegmental area. J. Neurosci. ate the dopamine activating and forcement and cognition restored alcohol consumption in heavy- 15, 5859–5869. reinforcing properties of ethanol by targeted expression of nicotinic drinking smokers. Psychopharma- Okamoto, T., Harnett, M. T., cues. Psychopharmacology (Berl.) receptors. Nature 436, 103–107. cology (Berl.) 223, 299–306. and Morikawa, H. (2006). 195, 333–343. Mason, B. J. (2003). Acamprosate Miyazawa, A., Fujiyoshi, Y., and Unwin, Hyperpolarization-activated cation Lopez-Moreno, J. A., Trigo-Diaz, J. M., and naltrexone treatment for N. (2003). Structure and gat- current (Ih) is an ethanol target Rodriguez de Fonseca, F., Gonzalez alcohol dependence: an evidence- ing mechanism of the acetyl- in midbrain dopamine neurons of Cuevas, G., Gomez de Heras, R., Cre- based risk-benefits assessment. choline receptor pore. Nature 423, mice. J. Neurophysiol. 95, 619–626. spo Galan, I., et al. (2004). Nico- Eur. Neuropsychopharmacol. 13, 949–955. Olausson, P.,Ericson, M., Lof, E., Engel, tine in alcohol deprivation increases 469–475. Mogg, A. J., Whiteaker, P., McIn- J. A., and Soderpalm, B. (2001). alcohol operant self-administration Mason, B. J., Goodman, A. M., Chabac, tosh, J. M., Marks, M., Collins, Nicotine-induced behavioral dis- during reinstatement. Neurophar- S., and Lehert, P. (2006). Effect of A. C., and Wonnacott, S. (2002). inhibition and ethanol preference macology 47, 1036–1044. oral acamprosate on abstinence in Methyllycaconitine is a potent correlate after repeated nicotine Lubke, G. H., Stephens, S. H., Lessem, patients with alcohol dependence in antagonist of alpha-conotoxin- treatment. Eur. J. Pharmacol. 417, J. M., Hewitt, J. K., and Ehringer, a double-blind, placebo-controlled MII-sensitive presynaptic nicotinic 117–123. M. A. (2012). The CHRNA5/A3/B4 trial: the role of patient motivation. acetylcholine receptors in rat stria- O’Malley, S. S., Jaffe, A. J., Chang, G., gene cluster and tobacco, alcohol, J. Psychiatr. Res. 40, 383–393. tum. J. Pharmacol. Exp. Ther. 302, Schottenfeld, R. S., Meyer, R. E., and cannabis, inhalants and other sub- Matsumoto, M., and Hikosaka, O. 197–204. Rounsaville, B. (1992). Naltrexone stance use initiation: replication and (2007). Lateral habenula as a Mokdad, A. H., Marks, J. S., Stroup, and coping skills therapy for alco- new findings using mixture analyses. source of negative reward signals D. F., and Gerberding, J. L. (2004). hol dependence. A controlled study. Behav. Genet. 42, 636–646. in dopamine neurons. Nature 447, Actual causes of death in the Arch. Gen. Psychiatry 49, 881–887. Lummis, S. C., Thompson, A. J., 1111–1115. United States, 2000. JAMA 291, Oslin, D. W., Berrettini, W. H., and Bencherif, M., and Lester, H. McGehee, D. S., Heath, M. J., Gel- 1238–1245. O’Brien, C. P. (2006). Targeting A. (2011). Varenicline is a ber, S., Devay, P., and Role, L. W. Morley, B. J. (1986). The interpeduncu- treatments for alcohol dependence: potent agonist of the human (1995). Nicotine enhancement of lar nucleus. Int. Rev. Neurobiol. 28, the pharmacogenetics of naltrexone. 5-hydroxytryptamine3 receptor. J. fast excitatory synaptic transmission 157–182. Addict. Biol. 11, 397–403. Pharmacol. Exp. Ther. 339, 125–131. in CNS by presynaptic receptors. Moroni, M., Zwart, R., Sher, E., Cas- Papke, R. L., Wecker, L., and Stitzel, Madden, P. A., and Heath, A. C. Science 269, 1692–1696. sels, B. K., and Bermudez, I. (2006). J. A. (2010). Activation and inhi- (2002). Shared genetic vulnerability McGehee, D. S., and Role, L. W. (1995). alpha4beta2 nicotinic receptors with bition of mouse muscle and neu- in alcohol and cigarette use and Physiological diversity of nicotinic high and low acetylcholine sen- ronal nicotinic acetylcholine recep- dependence. Alcohol. Clin. Exp. Res. acetylcholine receptors expressed by sitivity: pharmacology, stoichiom- tors expressed in Xenopus oocytes. J. 26, 1919–1921. vertebrate neurons. Annu. Rev. Phys- etry, and sensitivity to long-term Pharmacol. Exp. Ther. 333, 501–518. Mansvelder, H. D., Keath, J. R., iol. 57, 521–546. exposure to nicotine. Mol. Pharma- Pettinati, H. M., Anton, R. F., and Wil- and McGehee, D. S. (2002). McKee, S. A., Harrison, E. L., O’Malley, col. 70, 755–768. lenbring, M. L. (2006). The combine Synaptic mechanisms underlie S. S., Krishnan-Sarin, S., Shi, Nadal, R., Chappell, A. M., and study-: an overview of the largest nicotine-induced excitability of J., Tetrault, J. M., et al. (2009). Samson, H. H. (1998). Effects pharmacotherapy study to date for brain reward areas. Neuron 33, Varenicline reduces alcohol of nicotine and mecamylamine treating alcohol dependence. Psychi- 905–919. self-administration in heavy- microinjections into the nucleus atry (Edgmont) 3, 36–39. Margolis, E. B., Lock, H., Hjelmstad, drinking smokers. Biol. Psychiatry accumbens on ethanol and sucrose Picciotto, M. R., Zoli, M., Rimondini, G. O., and Fields, H. L. (2006a). 66, 185–190. self-administration. Alcohol. Clin. R., Lena, C., Marubio, L. M., Pich, The ventral tegmental area revis- Mereu, G., Fadda, F., and Gessa, G. L. Exp. Res. 22, 1190–1198. E. M., et al. (1998). Acetylcholine ited: is there an electrophysiological (1984). Ethanol stimulates the fir- Nagata, K., Aistrup, G. L., Huang, C. receptors containing the beta2 sub- marker for dopaminergic neurons? ing rate of nigral dopaminergic neu- S., Marszalec, W., Song, J. H., Yeh, unit are involved in the reinforcing J. Physiol. (Lond.) 577, 907–924. rons in unanesthetized rats. Brain J. Z., et al. (1996). Potent modu- properties of nicotine. Nature 391, Margolis, E. B., Lock, H., Chefer, V. I., Res. 292, 63–69. lation of neuronal nicotinic acetyl- 173–177. Shippenberg, T. S., Hjelmstad, G. O., Meyerhoff, D. J., Tizabi, Y., Staley, J. choline receptor-channel by ethanol. Pidoplichko, V. I., Noguchi, J., Areola, and Fields,H. L. (2006b). Kappa opi- K., Durazzo, T. C., Glass, J. M., Neurosci. Lett. 217, 189–193. O. O., Liang, Y., Peterson, J., Zhang, oids selectively control dopaminer- and Nixon, S. J. (2006). Smoking Nashmi, R., Xiao, C., Deshpande, T., et al. (2004). Nicotinic cholin- gic neurons projecting to the pre- comorbidity in alcoholism: neurobi- P., McKinney, S., Grady, S. R., ergic synaptic mechanisms in the frontal cortex. Proc. Natl. Acad. Sci. ological and neurocognitive conse- Whiteaker, P., et al. (2007). Chronic ventral tegmental area contribute to U.S.A. 103, 2938–2942. quences. Alcohol. Clin. Exp. Res. 30, nicotine cell specifically upregulates nicotine addiction. Learn. Mem. 11, Marszalec, W., Aistrup, G. L., and Nara- 253–264. functional alpha 4∗ nicotinic recep- 60–69. hashi, T. (1999). Ethanol-nicotine Mihalak, K. B., Carroll, F. I., and Luetje, tors: basis for both tolerance in Pons, S., Fattore, L., Cossu, G., Tolu, interactions at alpha-bungarotoxin- C. W. (2006). Varenicline is a par- midbrain and enhanced long-term S., Porcu, E., McIntosh, J. M., et insensitive nicotinic acetylcholine tial agonist at alpha4beta2 and a potentiation in perforant path. J. al. (2008). Crucial role of alpha4 receptors in rat cortical neu- full agonist at alpha7 neuronal nico- Neurosci. 27, 8202–8218. and alpha6 nicotinic acetylcholine rons. Alcohol. Clin. Exp. Res. 23, tinic receptors. Mol. Pharmacol. 70, Nelson, M. E., Kuryatov, A., Choi, C. receptor subunits from ventral 439–445. 801–805. H., Zhou, Y., and Lindstrom, J. tegmental area in systemic nicotine

Frontiers in Psychiatry | Addictive Disorders and Behavioral Dyscontrol April 2013 | Volume 4 | Article 29| 14 Hendrickson et al. Nicotinic receptors in alcohol dependence

self-administration. J. Neurosci. 28, T. J., McBride, W. J., et al. Samson, H. H., Tolliver, G. A., rats in a limited access paradigm. 12318–12327. (2010). Serotonin-3 receptors in the Haraguchi, M., and Hodge, C. W. Psychopharmacology (Berl.) 142, Pontieri, F. E., Tanda,G., Orzi, F.,and Di posterior ventral tegmental area reg- (1992). Alcohol self-administration: 408–412. Chiara, G. (1996). Effects of nicotine ulate ethanol self-administration of role of mesolimbic dopamine. Ann. Soderpalm, B., Ericson, M., Olaus- on the nucleus accumbens and sim- alcohol-preferring (P) rats. Alcohol N. Y. Acad. Sci. 654, 242–253. son, P., Blomqvist, O., and Engel, ilarity to those of addictive drugs. 44, 245–255. Santos, N., Chatterjee, S., Henry, A., J. A. (2000). Nicotinic mechanisms Nature 382, 255–257. Role,L.W.,and Berg,D. K. (1996). Nico- Holgate, J., and Bartlett, S. E. involved in the dopamine acti- Potthoff, A. D., Ellison, G., and Nelson, tinic receptors in the development (2012). The alpha5 neuronal nico- vating and reinforcing properties L. (1983). Ethanol intake increases and modulation of CNS synapses. tinic acetylcholine receptor subunit of ethanol. Behav. Brain Res. 113, during continuous administration Neuron 16, 1077–1085. plays an important role in the seda- 85–96. of amphetamine and nicotine, but Room, R. (2004). Smoking and tive effects of ethanol but does Spanagel, R. (2009). Alcoholism: a not several other drugs. Pharmacol. drinking as complementary behav- not modulate consumption in mice. systems approach from molecular Biochem. Behav. 18, 489–493. iours. Biomed. Pharmacother. 58, Alcohol. Clin. Exp. Res. 37, 655–662. physiology to addictive behavior. Rassnick, S., Stinus, L., and Koob, 111–115. Schlaepfer, I. R., Hoft, N. R., Collins, Physiol. Rev. 89, 649–705. G. F. (1993). The effects of 6- Saccone, N. L., Culverhouse, R. C., A. C., Corley, R. P., Hewitt, J. K., Steensland, P., Simms, J. A., Holgate, J., hydroxydopamine lesions of Schwantes-An, T. H., Cannon, Hopfer, C. J., et al. (2008). The Richards, J. K., and Bartlett, S. E. the nucleus accumbens and the D. S., Chen, X., and Cichon, CHRNA5/A3/B4 gene cluster vari- (2007). Varenicline, an alpha4beta2 mesolimbic dopamine system S. (2010). Giegling multiple ability as an important determinant nicotinic acetylcholine receptor par- on oral self-administration of independent loci at chromo- of early alcohol and tobacco initia- tial agonist, selectively decreases ethanol in the rat. Brain Res. 623, some 15q25.1 affect smoking tion in young adults. Biol. Psychiatry ethanol consumption and seeking. 16–24. quantity: a meta-analysis and 63, 1039–1046. Proc. Natl. Acad. Sci. U.S.A. 104, Rezvani, A. H., Overstreet, D. H., Yang, comparison with lung cancer and Schultz, W. (2004). Neural coding of 12518–12523. Y., Maisonneuve, I. M., Bandarage, COPD. PLoS Genet. 6:ii:e1001053. basic reward terms of animal learn- Stephens, S. H., Hoft, N. R. I., U. K., Kuehne, M. E., et al. (1997). doi:10.1371/journal.pgen.1001053 ing theory, game theory, micro- Schlaepfer, R., Young, S. E., Cor- Attenuation of alcohol consumption Sajja, R. K., Dwivedi, C., and Rahman, S. economics and behavioural ecol- ley, R. C., McQueen, M. B., et by a novel nontoxic ibogaine ana- (2010). Nicotinic ligands modulate ogy. Curr. Opin. Neurobiol. 14, al. (2012). Externalizing behav- logue (18-methoxycoronaridine) in ethanol-induced dopamine func- 139–147. iors are associated with SNPs in alcohol-preferring rats. Pharmacol. tion in mice. Pharmacology 86, Semba, K., and Fibiger, H. C. (1992). the CHRNA5/CHRNA3/CHRNB4 Biochem. Behav. 58, 615–619. 168–173. Afferent connections of the lat- gene cluster. Behav. Genet. 42, Rezvani, A. H., Slade, S., Wells, C., Petro, Sajja, R. K., and Rahman, S. (2011). erodorsal and the pedunculopon- 402–414. A., Lumeng, L., Li, T. K., et al. (2010). Lobeline and cytisine reduce vol- tine tegmental nuclei in the rat: a Swanson, L. W. (1982). The projec- Effects of sazetidine-A, a selective untary ethanol drinking behavior retro- and antero-grade transport tions of the ventral tegmental area alpha4beta2 nicotinic acetylcholine in male C57BL/6J mice. Prog. Neu- and immunohistochemical study. J. and adjacent regions: a combined receptor desensitizing agent on alco- ropsychopharmacol. Biol. Psychiatry Comp. Neurol. 323, 387–410. fluorescent retrograde tracer and hol and nicotine self-administration 35, 257–264. Sesack, S. R., and Pickel, V. M. (1992). immunofluorescence study in the in selectively bred alcohol-preferring Sajja, R. K., and Rahman, S. (2012). Prefrontal cortical efferents in the rat. Brain Res. Bull. 9, 321–353. (P) rats. Psychopharmacology (Berl.) Neuronal nicotinic receptor ligands rat synapse on unlabeled neuronal Tapper, A. R., McKinney, S. L., Nashmi, 211, 161–174. modulate chronic nicotine-induced targets of catecholamine terminals R., Schwarz, J., Deshpande, P., Rhodes, J. S., Best, K., Belknap, J. K., ethanol consumption in C57BL/6J in the nucleus accumbens septi and Labarca, C., et al. (2004). Nico- Finn, D. A., and Crabbe, J. C. (2005). mice. Pharmacol. Biochem. Behav. on dopamine neurons in the ventral tine activation of alpha4∗ recep- Evaluation of a simple model of 102, 36–43. tegmental area. J. Comp. Neurol. 320, tors: sufficient for reward, toler- ethanol drinking to intoxication in Salamone, J. D., and Correa, M. (2012). 145–160. ance, and sensitization. Science 306, C57BL/6J mice. Physiol. Behav. 84, The mysterious motivational func- Shabat-Simon, M., Levy, D., Amir, A., 1029–1032. 53–63. tions of mesolimbic dopamine. Neu- Rehavi, M., and Zangen, A. (2008). Theile, J. W., Morikawa, H., Gon- Rhodes, J. S., Ford, M. M., Yu, C. H., ron 76, 470–485. Dissociation between rewarding and zales, R. A., and Morrisett, R. Brown, L. L., Finn, D. A., Garland, T. Salas, R., Sturm, R., Boulter, J., and De psychomotor effects of opiates: A. (2011). GABAergic transmission Jr., et al. (2007). Mouse inbred strain Biasi, M. (2009). Nicotinic receptors differential roles for glutamate modulates ethanol excitation of ven- differences in ethanol drinking to in the habenulo-interpeduncular receptors within anterior and poste- tral tegmental area dopamine neu- intoxication. Genes Brain Behav. 6, system are necessary for nicotine rior portions of the ventral tegmen- rons. Neuroscience 172, 94–103. 1–18. withdrawal in mice. J. Neurosci. 29, tal area. J. Neurosci. 28, 8406–8416. Thorgeirsson, T. E., Gudbjartsson, D. Rodd, Z. A., Bell, R. L., Melendez, R. I., 3014–3018. Sharpe, A. L., and Samson, H. H. F., Surakka, I., Vink, J. M., Amin, Kuc, K. A., Lumeng, L., Li, T. K., et Salminen, O., Drapeau, J. A., McIn- (2002). Repeated nicotine injec- N., Geller, F., et al. (2010). Sequence al. (2004a). Comparison of intracra- tosh, J. M., Collins, A. C., Marks, tions decrease operant ethanol self- variants at CHRNB3-CHRNA6 and nial self-administration of ethanol M. J., and Grady, S. R. (2007). administration. Alcohol 28, 1–7. CYP2A6 affect smoking behavior. within the posterior ventral tegmen- Pharmacology of alpha-conotoxin Sherva, R., Kranzler, H. R., Yu, Y., Nat. Genet. 42, 448–453. tal area between alcohol-preferring MII-sensitive subtypes of nicotinic Logue, M. W., Poling, J., Arias, A. Tolu, S., Eddine, R., Marti, F., David, and Wistar rats. Alcohol. Clin. Exp. acetylcholine receptors isolated by J., et al. (2010). Variation in nico- V., Graupner, M., Pons, S., et al. Res. 28, 1212–1219. breeding of null mutant mice. Mol. tinic acetylcholine receptor genes is (2012). Co-activation of VTA DA Rodd, Z. A., Melendez, R. I., Bell, R. Pharmacol. 71, 1563–1571. associated with multiple substance and GABA neurons mediates nico- L., Kuc, K. A., Zhang, Y., Murphy, J. Salminen, O., Murphy, K. L., McIn- dependence phenotypes. Neuropsy- tine reinforcement. Mol. Psychiatry M., et al. (2004b). Intracranial self- tosh, J. M., Drago, J., Marks, M. J., chopharmacology 35, 1921–1931. 18, 382–393. administration of ethanol within the Collins, A. C., et al. (2004). Sub- Sine, S. M. (2002). The nicotinic recep- Tonstad, S., Tonnesen, P., Hajek, P., ventral tegmental area of male Wis- unit composition and pharmacol- tor ligand binding domain. J. Neuro- Williams, K. E., Billing, C. B., and tar rats: evidence for involvement of ogy of two classes of striatal presy- biol. 53, 431–446. Reeves, K. R. (2006). Effect of main- dopamine neurons. J. Neurosci. 24, naptic nicotinic acetylcholine recep- Smith, B. R., Horan, J. T., Gaskin, S., tenance therapy with varenicline 1050–1057. tors mediating dopamine release and Amit, Z. (1999). Exposure to on smoking cessation: a random- Rodd, Z. A., Bell, R. L., Oster, in mice. Mol. Pharmacol. 65, nicotine enhances acquisition of ized controlled trial. JAMA 296, S. M., Toalston, J. E., Pommer, 1526–1535. ethanol drinking by laboratory 64–71.

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True, W. R., Xian, H., Scherrer, J. theory of addiction. Psychol. Rev. 94, synaptic transmission onto in Xenopus laevis oocytes. Mol. F., Madden, P. A., Bucholz, K. K., 469–492. dopaminergic neurons in ventral Pharmacol. 54, 1124–1131. Heath, A. C., et al. (1999). Common Wonnacott, S. (1997). Presynaptic nico- tegmental area: role of mu-opioid genetic vulnerability for nicotine tinic ACh receptors. Trends Neurosci. receptors. Neuroscience 153, and alcohol dependence in men. 20, 92–98. 240–248. Conflict of Interest Statement: The Arch. Gen. Psychiatry 56, 655–661. World Health Organization. (2011). Yeomans, J. S., Mathur, A., and authors declare that the research was Tyndale, R. F. (2003). Genetics of alco- Department of Mental Health and Tampakeras, M. (1993). Rewarding conducted in the absence of any com- hol and tobacco use in humans. Ann. Substance Abuse, Global Status brain stimulation: role of tegmen- mercial or financial relationships that Med. 35, 94–121. Report on Alcohol 2011, World tal cholinergic neurons that activate could be construed as a potential con- Unwin, N. (2005). Refined structure of Health Organization, Department dopamine neurons. Behav. Neurosci. flict of interest. the nicotinic acetylcholine receptor of Mental Health and Substance 107, 1077–1087. at 4A resolution. J. Mol. Biol. 346, Abuse, Geneva. York, J. L., and Hirsch, J. A. (1995). Received: 29 January 2013; accepted: 16 967–989. Wouda, J. A., Riga, D., De Vries, W., Drinking patterns and health status April 2013; published online: 30 April Volpicelli, J. R., Alterman, A. I., Stegeman, M., van Mourik,Y.,Schet- in smoking and nonsmoking alco- 2013. Hayashida, M., and O’Brien, C. P. ters, D., et al. (2011). Varenicline holics. Alcohol. Clin. Exp. Res. 19, Citation: Hendrickson LM, Guildford (1992). Naltrexone in the treatment attenuates cue-induced relapse to 666–673. MJ and Tapper AR (2013) Neuronal of alcohol dependence. Arch. Gen. alcohol, but not nicotine seeking, Zhao-Shea, R., Liu, L., Soll, L. G., nicotinic acetylcholine receptors: common Psychiatry 49, 876–880. while reducing inhibitory response Improgo, M. R., Meyers, E. E., molecular substrates of nicotine and alco- Wang, J. C., Grucza, R., Cruchaga, C., control. Psychopharmacology (Berl.) McIntosh, J. M., et al. (2011). hol dependence. Front. Psychiatry 4:29. Hinrichs, A. L., Bertelsen, S., Budde, 216, 267–277. Nicotine-mediated activation of doi: 10.3389/fpsyt.2013.00029 J. P., et al. (2009). Genetic variation Wu, G., Tonner, P. H., and Miller, K. dopaminergic neurons in distinct This article was submitted to Frontiers in the CHRNA5 gene affects mRNA W. (1994). Ethanol stabilizes the regions of the ventral tegmental in Addictive Disorders and Behavioral levels and is associated with risk for open channel state of the Tor- area. Neuropsychopharmacology 36, Dyscontrol, a specialty of Frontiers in alcohol dependence. Mol. Psychiatry pedo nicotinic acetylcholine recep- 1021–1032. Psychiatry. 14, 501–510. tor. Mol. Pharmacol. 45, 102–108. Zuo, Y., Nagata, K., Yeh, J. Z., and Copyright © 2013 Hendrickson, Guild- Weiss,F.,Lorang,M. T.,Bloom,F.E.,and Xiao, C., Shao, X. M., Olive, M. F., Grif- Narahashi, T. (2004). Single-channel ford and Tapper. This is an open- Koob, G. F. (1993). Oral alcohol self- fin, W. C. III, Li, K. Y.,Krnjevic, K., et analyses of ethanol modulation access article distributed under the terms administration stimulates dopamine al. (2009). Ethanol facilitates gluta- of neuronal nicotinic acetylcholine of the Creative Commons Attribution release in the rat nucleus accumbens: matergic transmission to dopamine receptors. Alcohol. Clin. Exp. Res. 28, License, which permits use, distribution genetic and motivational determi- neurons in the ventral tegmental 688–696. and reproduction in other forums, pro- nants. J. Pharmacol. Exp. Ther. 267, area. Neuropsychopharmacology 34, Zwart, R., and Vijverberg, H. P. (1998). vided the original authors and source 250–258. 307–318. Four pharmacologically distinct are credited and subject to any copy- Wise, R. A., and Bozarth, M. A. Xiao, C., and Ye, J. H. (2008). Ethanol subtypes of alpha4beta2 nicotinic right notices concerning any third-party (1987). A psychomotor stimulant dually modulates GABAergic acetylcholine receptor expressed graphics etc.

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