# The dark side of addiction: Significance of environmental conditioning to negative reinforcement by EtOH in subjects with a dependence history

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $399,720

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10077806
- **Project number:** 5R01AA027555-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Friedbert Weiss
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,720
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077806

## Citation

> US National Institutes of Health, RePORTER application 10077806, The dark side of addiction: Significance of environmental conditioning to negative reinforcement by EtOH in subjects with a dependence history (5R01AA027555-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077806. Licensed CC0.

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