Robert Harvey

The glycine receptor (GlyR) is known to be critical for inhibitory neurotransmission in brainstem and spinal cord. Interestingly, in recent years much more attention has been focused on the presence of GlyRs in supraspinal regions. Previous studies have shown that GlyRs are potentiated by low and clinically-relevant concentrations of ethanol. Recent data from several laboratories have shown that GlyRs are important in the brain reward system and that α1 and α2 are the predominant subunits expressed in the nucleus accumbens (nAc). In the present study, we characterized the function of GlyRs in nAc and behavior in GlyR α2 subunit knockout (KOα2) mice. Because the GlyRα2 subunit gene is located on the X chromosome, all adult males used in the study were hemizygous (-/Y) for the Glra2 gene. KOα2 mice exhibited normal brain weight and basal locomotor activity. However, in the accelerating rotarod assay, the latency to fall was significantly increased in KOα2 mice compared to WT mice, indicating a difference in motor skill performance. Using electrophysiological recordings in isolated neurons, we showed that accumbal neurons in KOα2 mice exhibited smaller glycine-evoked currents (~100 pA at 1 mM of glycine) compared to C57BL/6J mice (WT) (~500 pA at 1 mM of glycine). Also, we found a decrease in the glycinergic synaptic currents in nAc of mice lacking α2 subunits. We also examined the effect of ethanol on sedation and drinking behaviors. When we assayed KOα2 mice for loss of the righting reflex (LORR) in presence of 3.5 g/kg of ethanol, we found a decrease in duration (27±4 min) of LORR compared to WT mice (37±2 min). Finally, using the drinking in the dark (DID) paradigm, we showed that KOα2 mice have higher ethanol consumption compared to WT mice. These results support the existence of the α2 subunit GlyRs in accumbal neurons. Regarding ethanol effects, we demonstrated differences in behavioral studies, indicating the importance of the GlyRα2 subunit as a target for alcohol in supraspinal regions. Thus, GlyRs containing the α2 subunit are a biologically relevant target for the regulation of the reward system and the rewarding properties of ethanol.