Increased Voluntary Alcohol Consumption in Mice Lacking GABA_B(1) Is Associated With Functional Changes in Hippocampal...

Gamma-aminobutyric acid type B receptor (GABA_BR) 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_BR using the 2-bottle choice paradigm. We found that GABA_B(1), 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_BR agonist GHB significantly reduced alcohol consumption in the GABA_B(1) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABA_BR and δ-containing GABA_A receptor (δ-GABA 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_AR δ subunit in the hippocampus of the GABA_B(1) KO alcohol-naïve mice that was associated with increased ɣ² subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABA_AR 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_AR occurring in the GABA_B(1) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABA_B(1) KO and WT mice because of previous involvement of GABA_BR 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_B(1) 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_B(1) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABA_AR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABA_B(1) KO mice. In addition, we documented that GABA_B(1) 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.