Alcohol misuse continues to be a public health problem and identifying effective medications for the treatment of alcohol use disorders remains a high priority for NIAAA (Li , 2006). Given the strong evidence that the nicotinic acetylcholine receptor (nAChR) system is involved in modulating alcohol effects and consumption, this system holds promise as a viable target for medications development for alcohol use disorders. Prior work in this area has been limited due to the lack of suitable and specific nAChR agents for human administration. The recent FDA approval of varenicline, a partial nicotinic agonist, presents an exciting opportunity to further our understanding of the role of nAChRs in human alcohol consumption, and to evaluate whether clinical trial investigations examining the efficacy of varenicline for alcohol use disorders should be pursued. Support for this project comes from a pilot investigation conducted by our group (see Section C.1.1). Using an established alcohol self-administration paradigm (O'Malley et al., 2002) that is sensitive to medication effects on alcohol consumption, we evaluated whether varenicline (2 mg/day) altered reactivity to a fixed low dose of alcohol (.03 g/dl priming drink) and subsequent ad-libitum consumption in heavy drinking smokers and non-smokers. Varenicline attenuated alcohol craving and subjective alcohol effects (e.g., subjective intoxication) in response to the priming drink, robustly reduced alcohol self-administration, and was well tolerated in heavy drinking smokers and non-smokers. These results mirror preclinical studies examining the effect of varenicline on ethanol seeking and consumption (Steensland et al., 2007). Building on this preliminary investigation, our primary goal in the current application is to conduct a dose ranging study of varenicline to determine which doses of varenicline are efficacious for reducing alcohol self- administration behavior, and are safe and well tolerated. Specifically, smokers and non-smokers who meet criteria for alcohol use disorders will be randomized to varenicline (0, 1.0, 2.0 mg/day), titrated to steady state levels over the course of 9 days, participate in our alcohol self-administration laboratory paradigm, and then assessed for 2-weeks following medication discontinuation. We hypothesize that varenicline (1.0, 2.0 mg/day) compared to placebo (0 mg/day) will decrease the number of drinks consumed during the self-administration period, and secondarily, will reduce subjective reactivity (e.g., alcohol craving) to the initial priming dose of alcohol. We also expect that varenicline will be safe and well tolerated during the titration period and in combination with alcohol in both smokers and non-smokers who meet criteria for alcohol use disorders. To our knowledge, this will be the first dose-ranging investigation of varenicline effects on human alcohol consumption. Results will provide important information concerning dose selection for future clinical trial investigations, evidence that the nicotinic system is a viable medications target for alcohol use disorders, and elucidate potential mechanisms for these effects.

Public Health Relevance

Given the strong evidence that the nicotinic acetylcholine receptor (nAChR) system is involved in modulating alcohol effects and consumption, this system holds promise as a viable target for medications development for alcohol use disorders. The recent FDA approval of varenicline, a partial nicotinic agonist, presents an exciting opportunity to further our understanding of the role of nAChRs in human alcohol consumption, and to evaluate whether clinical trial investigations examining the efficacy of varenicline for alcohol use disorders should be pursued. Using a laboratory paradigm, our primary goal in the current application is to conduct a dose-ranging study of varenicline to determine which doses of varenicline are efficacious for reducing alcohol self-administration behavior, and are safe and well tolerated in smokers and non-smokers who meet criteria for alcohol use disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017976-02
Application #
7923910
Study Section
Special Emphasis Panel (ZAA1-BB (03))
Program Officer
Fertig, Joanne
Project Start
2009-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$333,215
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Roberts, Walter; McKee, Sherry A (2018) Effects of varenicline on cognitive performance in heavy drinkers: Dose-response effects and associations with drinking outcomes. Exp Clin Psychopharmacol 26:49-57
Roberts, Walter; Shi, Julia M; Tetrault, Jeanette M et al. (2018) Effects of Varenicline Alone and in Combination With Low-dose Naltrexone on Alcohol-primed Smoking in Heavy-drinking Tobacco Users: A Preliminary Laboratory Study. J Addict Med 12:227-233
Roberts, Walter; Verplaetse, Terril L; Moore, Kelly E et al. (2018) A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco-deprived and -satiated smokers. Hum Psychopharmacol 33:e2660
Roberts, Walter; Harrison, Emily L R; McKee, Sherry A (2017) Effects of varenicline on alcohol cue reactivity in heavy drinkers. Psychopharmacology (Berl) 234:2737-2745
Verplaetse, Terril L; Weinberger, Andrea H; Oberleitner, Lindsay M et al. (2017) Effect of doxazosin on stress reactivity and the ability to resist smoking. J Psychopharmacol 31:830-840
Roberts, Walter; Verplaetse, Terril L; Moore, Kelly et al. (2017) Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms. J Psychopharmacol 31:906-914
Verplaetse, Terril L; Pittman, Brian P; Shi, Julia M et al. (2016) Effect of Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings. Alcohol Clin Exp Res 40:1567-76
Verplaetse, Terril L; Pittman, Brian P; Shi, Julia M et al. (2016) Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders. J Addict Med 10:166-73
McKee, Sherry A; Young-Wolff, Kelly C; Harrison, Emily L R et al. (2013) Longitudinal associations between smoking cessation medications and alcohol consumption among smokers in the International Tobacco Control Four Country survey. Alcohol Clin Exp Res 37:804-10
Udo, Tomoko; Harrison, Emily L R; Shi, Julia et al. (2013) A preliminary study on the effect of combined nicotine replacement therapy on alcohol responses and alcohol self-administration. Am J Addict 22:590-7

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