Alcohol is one of the most commonly abused drugs in the US, with 10% of the population affected by alcohol dependence at some point in their lives. There is a critical need for the development of new medications to help alcohol dependent patients reduce their alcohol use and promote abstinence. One of key predictors of relapse is severity of alcohol craving and urge to drink, which are thought to be due to classically conditioned states, and neuroadaptive changes associated with chronic alcohol consumption and abstinence. Potential targets for new medications include gamma-aminobutyric acid (GABA), glutamate, and opioid systems, which become dysregulated with chronic excessive alcohol consumption. In the current proposal, we will evaluate a kappa-opioid receptor antagonist, benzodiazepine-GABAA alpha1 receptor antagonists/partial agonists and modulators of metabotropic glutamate receptors, as potential AUD medications to reduce persistent alcohol seeking and compulsive drinking. The proposed studies will utilize a validated drinking procedure in baboons that combines classical and operant conditioning and models characteristic patterns of human problem drinking ('too much, too fast, too often'). The procedure consists of a sequence of separate behavioral contingencies, each of which is correlated with a unique cue, to form different links of a chain of responses that ultimately resul in alcohol reinforcement. This procedure allows examination of the relationships between alcohol seeking and self-administration responses during ongoing alcohol consumption, as well as the ability to study persistence cue-maintained behaviors during abstinence. We propose to examine test drug effects on alcohol-maintained behaviors under conditions of abstinence and alcohol availability, and different dosing regimens common to AUD treatment.
Aim 1 will determine whether test drugs selectively reduce alcohol seeking and alter patterns of self-administration during daily access to alcohol.
Aim 2 will determine whether test drugs facilitate extinction of alcohol-directed responding during ongoing alcohol access and during abstinence.
Aim 3 will determine whether initiation and maintenance of subchronic treatment with test drugs during abstinence selectively reduces seeking and intake upon return to alcohol access.
Aim 4 will determine incidence of side effects of test drugs administered under conditions of ongoing drinking and abstinence. Integration of the data from these aims will be used to determine the therapeutic potential of each drug. That is, a drug with therapeutic potential would reduce cue-maintained alcohol seeking during abstinence, reduce seeking and self-administration during ongoing alcohol access, and produce few side effects. Comparison of dose effect functions in the alcohol and control groups will provide a therapeutic index of each test drug under conditions of alcohol access and abstinence. These studies will provide important, new information on the differential behavioral efficacy of compounds that target receptor mechanisms relevant to compulsive alcohol use and relapse in humans.

Public Health Relevance

There is a critical need for the development of new medications for the treatment of alcoholism. Towards this goal, the project will focus on drugs that modulate opioid, GABA and glutamate neurotransmitter systems, which are disrupted by chronic alcohol drinking and dependence. The knowledge gained by examining the efficacy of these drugs to reduce behaviors associated with motivation to drink, as well as alcohol consumption, in long-term heavy drinking animals will ultimately improve treatments strategies for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA015971-06A1
Application #
8639331
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Egli, Mark
Project Start
2005-12-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$506,788
Indirect Cost
$193,956
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Holtyn, August F; Tiruveedhula, V V N Phani Babu; Stephen, Michael Rajesh et al. (2017) Effects of the benzodiazepine GABAA ?1-preferring antagonist 3-isopropoxy-?-carboline hydrochloride (3-ISOPBC) on alcohol seeking and self-administration in baboons. Drug Alcohol Depend 170:25-31
Lee, Mary R; Weerts, Elise M (2016) Oxytocin for the treatment of drug and alcohol use disorders. Behav Pharmacol 27:640-648
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Kaminski, Barbara J; Duke, Angela N; Weerts, Elise M (2012) Effects of naltrexone on alcohol drinking patterns and extinction of alcohol seeking in baboons. Psychopharmacology (Berl) 223:55-66
Kaminski, Barbara J; Goodwin, Amy K; Wand, Gary et al. (2008) Dissociation of alcohol-seeking and consumption under a chained schedule of oral alcohol reinforcement in baboons. Alcohol Clin Exp Res 32:1014-22