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

Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involvedin alcohol use disorders; however, the mechanisms by which this receptor modulatesalcohol drinking behavior remain murky. In this study, we investigate alcoholconsumption and preference in mice lacking functional GABABR using the 2-bottlechoice paradigm. We found that GABAB.1/, knockout (KO), and heterozygous (HZ) micedrank higher amounts of an alcoholic solution, preferred alcohol to water, and reachedhigher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates.The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB.1/HZ and WT but not in the KO mice. Next, because of a functional crosstalk betweenGABABR and d-containing GABAA receptor (d-GABAAR), we profiled d subunit mRNAexpression levels in brain regions in which the crosstalk was characterized. We found aloss of the alcohol-sensitive GABAAR d subunit in the hippocampus of the GABAB.1/KO alcohol-naïve mice that was associated with increased G2 subunit abundance.Electrophysiological recordings revealed that these molecular changes were associatedwith increased phasic inhibition, suggesting a potential gain of synaptic GABAARresponsiveness to alcohol that has been previously described in an animal model ofexcessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revertthe dramatic loss of hippocampal d-GABAAR occurring in the GABAB.1/ KO micebut rather exacerbated this condition. Finally, we profiled hippocampal neuroactivesteroids levels following acute alcohols administration in the GABAB.1/ KO and WTmice because of previous involvement of GABABR in the regulation of cerebral levels ofthese compounds. We found that systemic administration of alcohol (1.5 g/kg) did notproduce alcohol-induced neurosteroid response in the GABAB.1/ KO mice but elicitedan expected increase in the hippocampal level of progesterone and 3a,5a-THP in theWT controls. In conclusion, we show that genetic ablation of the GABAB.1/ subunit results in increased alcohol consumption and preference that were associated withfunctional changes in hippocampal GABAAR, suggesting a potential mechanism bywhich preference for alcohol consumption is maintained in the GABAB.1/ KO mice. Inaddition, we documented that GABAB.1/ deficiency results in lack of alcohol-inducedneurosteroids, and we discussed the potential implications of this finding in the contextof alcohol drinking and dependence.