AUTHOR=Floris Gabriele , Asuni Gino Paolo , Talani Giuseppe , Biggio Francesca , Pisu Maria Giuseppina , Zanda Mary Tresa , Contu Liliana , Maciocco Elisabetta , Serra Mariangela , Follesa Paolo 

TITLE=Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2022.893835

DOI=10.3389/fnbeh.2022.893835

ISSN=1662-5153

ABSTRACT=<p>Gamma-aminobutyric acid type B receptor (GABA<sub>B</sub>R) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABA<sub>B</sub>R using the 2-bottle choice paradigm. We found that GABA<sub>B(1)</sub>, knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABA<sub>B</sub>R agonist GHB significantly reduced alcohol consumption in the GABA<sub>B(1)</sub> HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABA<sub>B</sub>R and δ-containing GABA<sub>A</sub> receptor (δ-GABA<sub><italic>A</italic></sub>R), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABA<sub>A</sub>R δ subunit in the hippocampus of the GABA<sub>B(1)</sub> KO alcohol-naïve mice that was associated with increased ɣ<sup>2</sup> subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABA<sub>A</sub>R responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABA<sub>A</sub>R occurring in the GABA<sub>B(1)</sub> KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABA<sub>B(1)</sub> KO and WT mice because of previous involvement of GABA<sub>B</sub>R in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABA<sub>B(1)</sub> KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABA<sub>B(1)</sub> subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABA<sub>A</sub>R, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABA<sub>B(1)</sub> KO mice. In addition, we documented that GABA<sub>B(1)</sub> deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.</p>