Ethanol consumption and sedation are altered in mice lacking the glycine receptor α2 subunit

Abstract

Background and Purpose: The precise mechanism/s of action of ethanol, although studied for many years, are not well understood. Like other drugs of abuse, ethanol affects dopamine levels in the nucleus accumbens (nAc), an important region of the mesolimbic system, causing a reinforcing effect. It has been shown that glycine receptors (GlyRs) present in the nAc are potentiated by clinically relevant concentrations of ethanol, where α1 and α2 are the predominant subunits expressed. Experimental Approach: Using a combination of electrophysiology and behavioural assays, we studied the involvement of GlyR α2 subunits on the effects of low and high doses of ethanol, as well as on consumption using mice lacking the GlyR α2 sub-unit (male Glra2 −/Y and female Glra2 −/−). Key Results: GlyR α2 subunits exist in accumbal neurons, since the glycine-evoked currents and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) in Glra2 −/Y mice were drastically decreased. In behavioural studies, differences in etha-nol consumption and sedation were observed between wild-type (WT) and Glra2 knockout (KO) mice. Using the drinking in the dark (DID) paradigm, we found that Glra2 −/Y mice presented a binge-like drinking behaviour immediately when exposed to ethanol rather than the gradual consumption seen in WT animals. Interestingly, the effect of knocking out Glra2 in female (Glra2 −/−) mice was less evident, since WT female mice already showed higher DID. Conclusion and Implications: The differences in ethanol consumption between WT and KO mice provide additional evidence supporting the conclusion that GlyRs are biologically relevant targets for the sedative and rewarding properties of ethanol.

Background and Purpose The precise mechanism/s of action of ethanol, although studied for many years, are not well understood. Like other drugs of abuse, ethanol affects dopamine levels in the nucleus accumbens (nAc), an important region of the mesolimbic system, causing a reinforcing effect. It has been shown that glycine receptors (GlyRs) present in the nAc are potentiated by clinically relevant concentrations of ethanol, where alpha 1 and alpha 2 are the predominant subunits expressed. Experimental Approach Using a combination of electrophysiology and behavioural assays, we studied the involvement of GlyR alpha 2 subunits on the effects of low and high doses of ethanol, as well as on consumption using mice lacking the GlyR alpha 2 subunit (maleGlra2(-/Y)and femaleGlra2(-/-)). Key Results GlyR alpha 2 subunits exist in accumbal neurons, since the glycine-evoked currents and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) inGlra2(-/Y)mice were drastically decreased. In behavioural studies, differences in ethanol consumption and sedation were observed between wild-type (WT) andGlra2knockout (KO) mice. Using the drinking in the dark (DID) paradigm, we found thatGlra2(-/Y)mice presented a binge-like drinking behaviour immediately when exposed to ethanol rather than the gradual consumption seen in WT animals. Interestingly, the effect of knocking outGlra2in female (Glra2(-/-)) mice was less evident, since WT female mice already showed higher DID. Conclusion and Implications The differences in ethanol consumption between WT and KO mice provide additional evidence supporting the conclusion that GlyRs are biologically relevant targets for the sedative and rewarding properties of ethanol.