Commentary Involvement of neuronal b 2 subunit-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal: Implications for pharmacotherapies Steven J. Simmons BA and Thomas J. Gould PhD Department of Psychology, Neuroscience Program, Temple University, Philadelphia, PA, 19122, USA Received 3 January 2014, Accepted 14 April 2014 Keywords: nicotine reward, nicotine withdrawal, nicotinic acetylcholine receptor, smoking cessation, b 2 subunit SUMMARY What is known and objective: Tobacco smoking remains a major health problem. Nicotine binds to nicotinic acetylcholine recep- tors (nAChRs), which can cause addiction and withdrawal symptoms upon cessation of nicotine administration. Pharma- cotherapies for nicotine addiction target brain alterations that underlie withdrawal symptoms. This review will delineate the involvement of the b 2 subunit of neuronal nAChRs in nicotine reward and in generating withdrawal symptoms to better understand the efficacy of smoking cessation pharmacothera- pies. Comment: Chronic nicotine desensitizes and upregulates b 2 subunit-containing nAChRs, and the prolonged upregulation of receptors may underlie symptoms of withdrawal. Experimen- tal research has demonstrated that the b 2 subunit of neuronal nAChRs is necessary for generating nicotine reward and with- drawal symptoms. What is new and conclusion: Smoking cessation pharmacother- apies act on b 2 subunit-containing nAChRs to reduce nicotine reward and withdrawal symptom severity. WHAT IS KNOWN AND OBJECTIVE Introduction Tobacco use is the leading cause of preventable death and disease in the United States, causing approximately 443 000 premature deaths each year. 1 The health impacts of tobacco use include increased risk of lung and oral cancers, coronary heart disease and stroke. 2 Nicotine addiction is expensive for individuals and the national economy, costing approximately $96Á8 billion annually in productivity loss. 3 Approximately 70% of smokers report desiring to quit, but only 42% of smokers actually attempt to quit smoking. Of those who attempt to quit, only 3–5% are successful after 6 months when the quit attempt is unaided by behavioural treatments or pharmacotherapies. 4 Clearly, tobacco smoking remains a major health problem for the United States and other countries. Nicotine is one of the principal psychoactive and addictive drugs in tobacco products. Similarly to other drugs of abuse, nicotine addiction is characterized by compulsive use, craving, tolerance from continued use and withdrawal upon cessation. 5 The symptoms of nicotine withdrawal include dysphoria, irritability, frustration and difficulty concentrating. 6 Smokers are able to relieve symptoms of withdrawal by relapsing. 7–9 These effects and the health consequences of tobacco smoking point to the impor- tance for a better understanding of the neurobiology of nicotine addiction. 10 Nicotine alters neurobiological processes by binding to neuronal nicotinic acetylcholine receptors (nAChRs). Similarly to other drugs of abuse, acute nicotine administration causes signalling changes in brain reward substrates, such as increasing the phasic release of mesolimbic dopamine (DA). 11–15 Chronic nicotine leads to desensitization and upregulation of neuronal nAChRs, includ- ing heteropentameric b 2 subunit-containing nAChRs. 16–23 During nicotine withdrawal, changes in both brain reward and neuronal nAChR functioning have been observed, which underlie with- drawal symptom development. 21,24–28 It is evident that the b 2 subunit of neuronal nAChRs is pivotal for the generation of reward from nicotine administration 29–35 as well as for the generation of cognitive and affective withdrawal symptoms. 36–41 Objective This review will focus on how b 2 subunit-containing nAChRs underlie the symptoms of nicotine withdrawal, as well as how these receptors underlie the rewarding and reinforcing properties of nicotine. Moreover, this review will discuss the utility of pharmacotherapies in reducing withdrawal symptom severity and the rewarding properties of nicotine via acting on b 2 subunit- containing nAChRs. The review will incorporate findings from human and animal studies to elucidate the involvement of the b 2 subunit in nicotine reward and withdrawal. COMMENT Nicotine in the brain: effects of chronic use and withdrawal Neuronal nicotinic acetylcholine receptors. Nicotine and endogenous acetylcholine (ACh) bind to pentameric nicotinic acetylcholine receptors (nAChRs), which are formed from a combination of a and b subunits, to gate the transmembrane flow of cations. 42,43 In the mammalian central nervous system, predominant nAChRs include low-affinity homomeric a 7 and high-affinity heteromeric a 4 b 2 nAChRs. The b 2 subunit can couple with non-a 4 subunits, including a 2 , a 3 and a 6 subunits to form functionally distinct nAChRs, but these receptors are much less densely expressed in Correspondence: Thomas J. Gould; Department of Psychology, Weiss Hall, Temple University, Philadelphia, PA, 19122, USA. Tel.: (215) 204 7495; fax: (215) 204 5539; e-mail: tgould@temple.edu © 2014 John Wiley & Sons Ltd 1 Journal of Clinical Pharmacy and Therapeutics, 2014 doi: 10.1111/jcpt.12171