Reduced sedation and increased ethanol consumption in knock-in mice expressing an ethanol insensitive alpha 2 subunit of the glycine receptor

Previous studies have shown the presence of several subunits of the inhibitory glycine receptor (GlyR) in the reward system, specifically in medium spiny neurons (MSNs) of the nucleus Accumbens (nAc). It was suggested that GlyR alpha 1 subunits regulate nAc excitability and ethanol consumption. However, little is known about the role of the alpha 2 subunit in the adult brain since it is a subunit highly expressed during early brain development. In this study, we used genetically modified mice with a mutation (KR389-390AA) in the intracellular loop of the GlyR alpha 2 subunit which results in a heteromeric alpha 2 beta receptor that is insensitive to ethanol. Using this mouse model denoted knock-in alpha 2 (KI alpha 2), our electrophysiological studies showed that neurons in the adult nAc expressed functional KI GlyRs that were rather insensitive to ethanol when compared with WT GlyRs. In behavioral tests, the KI alpha 2 mice did not show any difference in basal motor coordination, locomotor activity, or conditioned place preference compared with WT littermate controls. In terms of ethanol response, KI alpha 2 male mice recovered faster from the administration of ataxic and sedative doses of ethanol. Furthermore, KI alpha 2 mice consumed higher amounts of ethanol in the first days of the drinking in the dark protocol, as compared with WT mice. These results show that the alpha 2 subunit is important for the potentiation of GlyRs in the adult brain and this might result in reduced sedation and increased ethanol consumption.

Automated summary

The alpha 2 subunit of the inhibitory glycine receptor is important for enhancing GlyRs in the adult brain, potentially leading to reduced sedation and increased ethanol consumption.