# GABA-A receptor subtype mechanisms and the abuse-related effects of alcohol > **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $471,208 ## Abstract The abuse of alcohol is controlled by multiple effects of the drug, including its subjective, reinforcing, and re- lapse-inducing effects. Preclinical methods have been developed to assess the contribution of these control- ling factors and their neurobiological underpinnings, and to provide empirically based models for evaluating potential treatment strategies. Alcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the abuse-related effects of alcohol in both humans and laboratory animals, making this system an attractive candidate for the development of thera- peutics. The complex molecular biology of GABAA receptors raises the possibility that subtype-selective agents might be developed with therapeutic specificity against alcohol. In this application, we will investigate the role of γ- and δ-containing α4GABAA and α6GABAA receptor mechanisms in nonhuman primate and rodent models of the abuse-related effects of alcohol. We will use first-in-kind compounds that are selective for α4δ, α6δ, α4γ, and/or α6γGABAA receptors to investigate the contribution of these subtypes to: 1) the discriminative stimulus effects of alcohol in monkeys trained to discriminate intra-gastrically-administered alcohol from vehi- cle, 2) the reinforcing effects of alcohol in monkeys orally self-administering alcohol, and 3) the relapse- inducing effects of alcohol in rats trained in either cue-induced reinstatement or alcohol deprivation effect pro- cedures (Specific Aim 1). Understanding the neuropharmacological mechanisms underlying the addictive ef- fects of alcohol is an important initial step in the development of candidate pharmacotherapies for the treat- ment of alcohol abuse and dependence. The degree to which the effects of γ- and δ-selective α4GABAA and α6GABAA ligands selectively modify alcohol-controlled behavior will be evaluated in monkeys that self- administer a sucrose solution instead of alcohol and in rats trained in a cue-induced sucrose seeking proce- dure. In monkeys, concurrent observational studies will characterize the effects of the ligands, alone or com- bined with alcohol, on unconditioned motor behavior (Specific Aim 2). The ability of these ligands to mimic or modulate the discriminative stimulus effects of alcohol, alcohol self-administration, and cue-induced alcohol seeking and relapse-like drinking at doses that do not produce a generalized disruption of behavior or debilitat- ing side effects may be predictive of potential therapeutic utility. Finally, we will investigate the utility of selec- tive GABAergic ligands with favorable side effect profiles to serve as co-therapies in a model of medication- assisted treatment (Specific Aim 3). These studies will make use of a novel resurgence model of contingency management developed recently in our laboratory and, initially, ligands that either mimic or attenuate the be- havioral effects of alcohol. Integ... ## Key facts - **NIH application ID:** 10151929 - **Project number:** 1R01AA029023-01 - **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR - **Principal Investigator:** Donna M Platt - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $471,208 - **Award type:** 1 - **Project period:** 2020-09-15 → 2025-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10151929 ## Citation > US National Institutes of Health, RePORTER application 10151929, GABA-A receptor subtype mechanisms and the abuse-related effects of alcohol (1R01AA029023-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151929. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*