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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA012870-14
Application #
8668816
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
14
Fiscal Year
2014
Total Cost
$192,169
Indirect Cost
$53,725
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chang, Fong; Xu, Ke; Huang, Ming-Chyi et al. (2017) Alcohol Triggers Reemergence of Ketamine-Like Experience in a Ketamine Ex-User. J Clin Psychopharmacol 37:110-112
Wang, Qian; Polimanti, Renato; Kranzler, Henry R et al. (2017) 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 136:75-83
Kort, Naomi S; Ford, Judith M; Roach, Brian J et al. (2017) Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia. Biol Psychiatry 81:514-524
Krystal, John H; Petrakis, Ismene L; O'Malley, Stephanie et al. (2017) NMDA Glutamate Receptor Antagonism and the Heritable Risk for Alcoholism: New Insights from a Study of Nitrous Oxide. Int J Neuropsychopharmacol 20:351-353
Polimanti, Renato; Gelernter, Joel (2017) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet :
Polimanti, Renato; Jensen, Kevin P; Gelernter, Joel (2017) Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers. Sci Rep 7:1034
Polimanti, Renato; Agrawal, Arpana; Gelernter, Joel (2017) Schizophrenia and substance use comorbidity: a genome-wide perspective. Genome Med 9:25
Polimanti, Renato; Gelernter, Joel; Stein, Dan J (2017) Genetically determined schizophrenia is not associated with impaired glucose homeostasis. Schizophr Res :
Polimanti, Renato; Wang, Qian; Meda, Shashwath A et al. (2017) The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene. Neuropsychopharmacology 42:598-605
Polimanti, Renato; Meda, Shashwath A; Pearlson, Godfrey D et al. (2017) S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours. J Psychiatry Neurosci 42:252-261

Showing the most recent 10 out of 249 publications