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Overexpression of wild type glycine alpha 1 subunit rescues ethanol sensitivity in accumbal receptors and reduces binge drinking in mice

Abstract

The nucleus accumbens (nAc) is a critical region in the brain reward system since it integrates abundant synaptic inputs contributing to the control of neuronal excitability in the circuit. The presence of inhibitory α1 glycine receptor (GlyRs) subunits, sensitive to ethanol, has been recently reported in accumbal neurons suggesting that they are protective against excessive binge consumption. In the present study, we used viral vectors (AAV) to overexpress mutant and WT α1 subunits in accumbal neurons in D1 Cre and α1 KI mice. Injection of a Cre-inducible AAV carrying an ethanol insensitive α1 subunit in D1 Cre neurons was unable to affect sensitivity to ethanol in GlyRs or affect ethanol drinking. On the other hand, using an AAV that transduced WT α1 GlyRs in GABAergic neurons in the nAc of high-ethanol consuming mice caused a reduction in ethanol intake as reflected by lowered drinking in the dark and reduced blood ethanol concentration. As expected, the AAV increased the glycine current density by 5-fold without changing the expression of GABAA receptors. Examination of the ethanol sensitivity in isolated accumbal neurons indicated that the GlyRs phenotype changed from an ethanol resistant to an ethanol sensitive type. These results support the conclusion that increased inhibition in the nAc can control excessive ethanol consumption and that selective targeting of GlyRs by pharmacotherapy might provide a mechanistic procedure to reduce ethanol binge.

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Fig. 1: Effects of overexpressing GlyRα1KI in D1-Cre mice in accumbal neurons.
Fig. 2: Ethanol consumption behavior in D1-Cre mice that overexpressed the GlyRα1KI in the nAc.
Fig. 3: Overexpression of α1 GlyRs in accumbal neurons of KIα1 mice.
Fig. 4: Overexpression of α1 WT GlyRs in KIα1 mice recovered the sensitivity to ethanol in dissociated accumbal neurons.
Fig. 5: Effect of GlyRs α1WT overexpression in the nAc of KIα1 mice on ethanol consumption behavior.

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Acknowledgements

We thank Lauren Aguayo and Carolina Benitez for technical assistance. To https://smart.servier.com for templates for illustrations.

Funding

This work was supported by the National Institutes of Health (NIH) grant R01AA025718, FONDECYT 1211082, FONDECYT 1201577, Beca Doctorado Nacional ANID 21190807.

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AA and LA participated in the research design. AA, MR, AM and RC designed and generated AAVs. AA, SG, and AM performed the experiments and analyzed the data. AA, SG, MKL and LA wrote or contributed to the writing of the manuscript. All authors reviewed the manuscript.

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Correspondence to Luis G. Aguayo.

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Araya, A., Gallegos, S., Maldonado, A. et al. Overexpression of wild type glycine alpha 1 subunit rescues ethanol sensitivity in accumbal receptors and reduces binge drinking in mice. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01459-2

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