Alcohol use disorders impact millions of individuals and constitute one of the most serious public health problems worldwide. Despite its devastating impact on society, there are still few effective medications currently available. It is well-known that alcohol and nicotine are commonly abused together, and that ethanol and nicotine have direct affects on neuronal nicotinic acetylcholine receptors (nAChRs). These receptors have been shown to modulate the mesolimbic dopamine system and contribute to the reinforcing actions of both ethanol and nicotine. The nAChRs are pentameric ligand-gated ion channels and in the CNS there are at least twelve receptors, designated 12 to 110, and 22 to 24 that assemble into multiple combinations. My lab discovered that varenicline, a drug that primarily binds to 1422 nAChRs and approved by the FDA as a smoking cessation aid, reduces ethanol self-administration and heavy drinking following long-term ethanol exposure. We will determine the consequences of long-term ethanol exposure on the role and expression of 1422 nAChRs following voluntary heavy ethanol consumption, operant self-administration and in stress- induced reinstatement. We will integrate behavioral and biochemical techniques to identify the brain regions mediating the effects of long-term ethanol exposure on the expression of nAChRs. The long-term goal is to design better therapeutic agents that target nAChRs for the treatment of alcohol use disorders.

Public Health Relevance

Alcohol use disorders are one of the most serious public health problems worldwide. Neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to contribute to the effects of ethanol. We found that varenicline, a modulator of 1422 nAChRs and recently approved as an aid for smoking cessation, reduces ethanol self-administration and heavy drinking following long-term but not short-term ethanol exposure. We will determine whether long-term ethanol exposure induces changes in the expression of 1422 nAChRs and whether this contributes to the reinforcing effects of ethanol and/or stress-induced relapse. The long-term goal is to design more selective and effective medications for the treatment of alcohol use disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017924-02
Application #
7994236
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Egli, Mark
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
2
Fiscal Year
2011
Total Cost
$377,234
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Feduccia, A A; Simms, J A; Mill, D et al. (2014) Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens. Br J Pharmacol 171:3420-31
Santos, Nathan; Chatterjee, Susmita; Henry, Andrea et al. (2013) The α5 neuronal nicotinic acetylcholine receptor subunit plays an important role in the sedative effects of ethanol but does not modulate consumption in mice. Alcohol Clin Exp Res 37:655-62
Chatterjee, Susmita; Santos, Nathan; Holgate, Joan et al. (2013) The α5 subunit regulates the expression and function of α4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area. PLoS One 8:e68300
Simms, Jeffrey A; Haass-Koffler, Carolina L; Bito-Onon, Jade et al. (2012) Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology 37:906-18
Feduccia, Allison A; Chatterjee, Susmita; Bartlett, Selena E (2012) Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions. Front Mol Neurosci 5:83
Nielsen, Carsten K; Simms, Jeffrey A; Bito-Onon, Jade J et al. (2012) The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking. Addict Biol 17:224-34
Chatterjee, Susmita; Steensland, Pia; Simms, Jeffrey A et al. (2011) Partial agonists of the α3β4* neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats. Neuropsychopharmacology 36:603-15
Bito-Onon, Jade J; Simms, Jeffrey A; Chatterjee, Susmita et al. (2011) Varenicline, a partial agonist at neuronal nicotinic acetylcholine receptors, reduces nicotine-induced increases in 20% ethanol operant self-administration in Sprague-Dawley rats. Addict Biol 16:440-9
Simms, Jeffrey A; Richards, Jemma K; Mill, Douglas et al. (2011) Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long-Evans rats by the ýý-2 adrenoreceptor antagonist yohimbine. Psychopharmacology (Berl) 218:101-10
Simms, Jeffrey A; Bito-Onon, Jade J; Chatterjee, Susmita et al. (2010) Long-Evans rats acquire operant self-administration of 20% ethanol without sucrose fading. Neuropsychopharmacology 35:1453-63

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