The conditioning of ethanol?s (EtOH) reinforcing effects with environmental stimuli is a major factor in the abuse potential of this drug. EtOH-related stimuli elicit strong EtOH seeking in animal models of relapse and these models are widely employed to study the neurobiological basis of EtOH craving and relapse. However, behavioral and neurobiological information on conditioning factors in EtOH seeking derived from animal models is limited to that from EtOH nondependent animals or, in animals with a dependence history, use of stimuli conditioned to the reinforcing effects of EtOH before dependence induction without consideration of conditioning factors related specifically to EtOH consumption in the dependent state. In alcoholics, a significant positive correlation exists between the history and degree of dependence and the severity of drinking urges induced by alcohol-related environmental stimuli. One process to explain this observation is that repeated consumption of EtOH during withdrawal states allows for learning of the negative contingency between EtOH consumption and adverse withdrawal symptoms, modifying an individual?s reinforcement history to include learning about amelioration/avoidance of adverse states as a novel and essential aspect of EtOH?s reinforcing actions. This proposal is designed to address the implications of this process with regard to EtOH craving and relapse, with the major hypothesis that a consequence of withdrawal-related learning (WDL) the conditioned effects of EtOH- associated environmental stimuli come to exert more powerful control over EtOH-directed behavior than stimuli conditioned to the positive reinforcing effects alone, and thereby play a dominant role in eliciting and maintaining compulsive EtOH seeking. In support of this hypothesis, preliminary data that provide the basis for this proposal show that stimuli conditioned to EtOH availability during withdrawal (WDL) elicit significant reinstatement in a manner that is punishment- and effort- resistant, whereas EtOH seeking induced by stimuli conditioned to EtOH in the nondependent state in rats without a withdrawal-related learning (N-WDL) history is not. The purpose of the proposed project is to solidify and extend the preliminary findings across three Specific Aims: (1) to establish the significance of environmental conditioning to withdrawal relief by EtOH (WDL) in initiating and maintaining compulsive EtOH seeking, (2) to identify neuronal ensembles mediating compulsive ethanol seeking linked to WDL and to confirm their role in this behavior via activity-dependent pharmacogenetic neural inactivation, and (3) to establish the neurochemical/phenotypic profile of behaviorally critical neuronal ensembles in WDL- vs. N- WDL-motivated EtOH seeking utilizing RNAscope. Successful completion of this project is expected to establish WDL as a major previously not well recognized factor in relapse vulnerability and provide the necessary foundations for future studies to uncover the learning and neuroadaptive and mechanisms responsible for the control of EtOH seeking by stimuli linked to WDL.

Public Health Relevance

This proposal addresses the need for better understanding of the neurobehavioral basis of the compulsive and chronically relapsing nature of alcohol addiction. Neurobiological and medications development information from animal models of relapse to alcohol use is limited largely to studies in alcohol nondependent animals. To advance understanding of the alcohol addiction process and ultimately improve treatment strategies, the proposed studies will investigate the significance of a previously not well recognized but presumably major factor in relapse vulnerability: the effects of stimuli conditioned to the potent addictive dimensions of alcohol associated with alcohol consumption to ameliorate withdrawal distress and neurobiological basis of these stimulus effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA027555-02
Application #
10077806
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2020-01-01
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037