Alcohol dependence is a chronic, relapsing disorder and the development of medications for this disorder has been based on a systematic understanding of the neurochemical processes mediating alcohol drinking behaviors. There is extensive evidence for a role for the glutamatergic and opioidergic systems in alcohol reward processes. In CTNA1 we showed for the first time that the efficacy of in reducing drinking is only observed in drinkers with a positive family history of alcoholism (FHP) and not in those with a negative family history of alcoholism (FHN);interestingly, this reduction in drinking was accompanied by very modest reductions in alcohol craving and no effects on alcohol-induced stimulation. In CTNA2 we conducted a similar examination using the glutatmatergic agent memantine, and again observed effects only in FHP but not in FHN drinkers;interestingly memantine appears to reduce alcohol stimulation and alcohol craving with modest effects on alcohol drinking. This exciting evidence suggests that glutamatergic and opioidergic agents may target different behavioral processes involved in alcohol drinking. Habitual alcohol use in alcohol dependent heavy drinkers may be dependent not just on continued alcohol reward but also on conditioned incentive processes, like cue-induced craving and automated motivational tendencies, which are mediated by complex interactions between different neurochemical processes, and could be targeted differentially by memantine and naltrexone. In CTNA3 we will conduct a """"""""proof of concept"""""""" Phase I evaluation to examine the effect of combined treatment with naltrexone and memantine on alcohol drinking and alcohol reward as measured using alcohol-induced stimulation and craving, in non-treatment seeking, alcohol dependent, heavy drinkers with a positive family history of alcoholism. Exploratory aims will also evaluate the influence of these medications on automated motivational tendencies towards alcohol drinking and also examine the influences of novel behavioral (Pavlovian to Instrumental transfer task) and genetic (Striatally enriched phosphates Fyn kinas) predictors on treatment response.

Public Health Relevance

Alcohol dependence is a chronic relapsing disorder and we need new medications to help heavy drinkers stop drinking. This project will test the combined use of two medications, naltrexone and memantine, in reducing alcohol drinking and alcohol reward.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Krystal, John H (2016) Neuroethology as a translational neuroscience strategy in the era of the NIMH Research Domain Criteria. Psychophysiology 53:364-6
Clarke, Toni-Kim; Smith, Andrew H; Gelernter, Joel et al. (2016) Polygenic risk for alcohol dependence associates with alcohol consumption, cognitive function and social deprivation in a population-based cohort. Addict Biol 21:469-80
Duman, Ronald S; Aghajanian, George K; Sanacora, Gerard et al. (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238-49
Wang, Fan; Xu, Hongqin; Zhao, Hongyu et al. (2016) DNA co-methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders. Sci Rep 6:19430
Tsai, Wan-Min; Zhang, Heping; Buta, Eugenia et al. (2016) A modified classification tree method for personalized medicine decisions. Stat Interface 9:239-253
Wrocklage, Kristen M; Schweinsburg, Brian C; Krystal, John H et al. (2016) Neuropsychological Functioning in Veterans with Posttraumatic Stress Disorder: Associations with Performance Validity, Comorbidities, and Functional Outcomes. J Int Neuropsychol Soc 22:399-411
Wang, Qian; Polimanti, Renato; Kranzler, Henry R et al. (2016) Genetic factor common to schizophrenia and HIV infection is associated with risky sexual behavior: antagonistic vs. synergistic pleiotropic SNPs enriched for distinctly different biological functions. Hum Genet :
Steele, Vaughn R; Anderson, Nathaniel E; Claus, Eric D et al. (2016) Neuroimaging measures of error-processing: Extracting reliable signals from event-related potentials and functional magnetic resonance imaging. Neuroimage 132:247-60
Morean, M E; Zellers, S; Tamler, M et al. (2016) Psychometric validation of measures of alcohol expectancies, retrospective subjective response, and positive drinking consequences for use with adolescents. Addict Behav 58:182-7
Arout, Caroline A; Perrino Jr, Albert C; Ralevski, Elizabeth et al. (2016) Effect of Intravenous Ethanol on Capsaicin-Induced Hyperalgesia in Human Subjects. Alcohol Clin Exp Res 40:1425-9

Showing the most recent 10 out of 230 publications