Neurosteroid Binding Sites on the GABA_AReceptor Complex as Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence

Abstract

Despite the prevalence of alcohol abuse and dependence in the US and Europe, there are only five approved pharmacotherapies for alcohol dependence. Moreover, these pharmacotherapeutic options have limited clinical utility. The purpose of this paper is to present pertinent literature suggesting that both alcohol and the neurosteroids interact at the GABAA receptor complex and that the neurosteroid sites on this receptor complex could serve as new targets for the development of novel therapeutics for alcohol abuse. This paper will also present data collected by our laboratory showing that one neurosteroid in particular, dehydroepiandrosterone (DHEA), decreases ethanol intake in rats under a variety of conditions. In the process, we will also mention relevant studies from the literature suggesting that both particular subtypes and subunits of the GABAA receptor play an important role in mediating the interaction of neurosteroids and ethanol.

Maternal care‐related differences in males and females rats’ sensitivity to ethanol and the associations between the GABAergic system and steroids in males

“…Operant self-administration as employed in the mice studies (Cruz et al, 2008; García-Gutiérrez et al, 2016) measures motivation (June & Gilpin, 2010), while our two-bottle choice paradigm better measures ethanol preference (Rhodes et al, 2005). Moreover, a previous study (Hulin, Amato, Porter, Filipeanu, & Winsauer, 2011) reported that the two paradigms, (i.e., ethanol self-administration in the home cage versus operant chamber), produced very different ethanol intake patterns. Nevertheless, our results corroborate some existing results suggesting that reduced maternal care may not affect adolescent ethanol consumption and preference in rats.…”

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction

“…For example, metyrapone may also increase dehydroepiandrosterone (DHEA), an androgenic precursor and one of the most abundant steroid metabolites, possessing both genomic and nongenomic actions [56,73,95,96]. DHEA has also been demonstrated to decrease cocaine-and alcoholrelated behaviors and may contribute to the efficacy of metyrapone [97][98][99][100].…”

Probing the Manipulated Neurochemical Drive in Alcohol Addiction and Novel Therapeutic Advancements

“…As high ethanol intake promotes neurosteroid synthesis, they are capable of activating GABA-A receptors even at nanomolar concentrations . For a competitive GABA-A receptor antagonist (SR 95531), when administered directly into the central nucleus of the amygdala, a decrease in alcohol intake was observed . Thus, neurosteroids could be a potential target in alcoholic patients due to their vital role in regulating the activity of GABA-A receptors.…”