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Common Molecular Substrates of Nicotine and Alcohol Dependence University of Massachusetts Medical School eScholarship@UMMS University of Massachusetts Medical School Faculty Publications 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. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/faculty_pubs Part of the Mental Disorders Commons, Psychiatry Commons, and the Substance Abuse and Addiction Commons 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 g-amino butyric tleton et al., 2007). Many hypotheses have been proposed as to the acid (GABA, the GABAA, and GABAC receptor), glycine, and www.frontiersin.org April 2013 | Volume 4 | Article 29 | 1 Hendrickson et al. Nicotinic receptors in alcohol dependence 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 a subunits (a7-a9) or heteromeric residues (Cys-loop) in their extracellular amino terminus (Karlin, receptors that contain a and b subunits (a2- a6 and b2-b4) (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 a7 homomeric and high affinity ligand-gated ion channels are formed by the arrangement of five a4b2∗ heteromeric nAChRs. An asterisk in nAChR nomenclature subunits to create a central pore (Albuquerque et al., 2009). The (i.e.,a4∗,a4b2∗) indicates that other unidentified nAChR subunits structure of neuronal nAChRs is homologous to muscle nAChRs may also be present and can be read as “a4 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, a4b2 nAChRs can nAChR gene encodes a protein subunit consisting of a large amino- be formed by either two a and three b subunits [(a4)2(b2)3] or terminal extracellular domain composed of b-strands, four trans- three a and two b subunits [(a4)3(b2)2](Zwart and Vijverberg, membrane a-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: [(a4)2(b2)3] (Corringer et al., 2000)(Figure 1A). The extracellular N-terminus nAChRs have a higher sensitivity to agonist (EC50 D s1 mM ACh); contains the ACh binding domain that forms a hydrophobic whereas [(a4)3(b2)2] nAChRs have a lower sensitivity to ago- pocket located between adjacent subunits in an assembled recep- nist (EC50 D s100 mM 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
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