Dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of schizophrenia and drug addiction. Two transgenic mouse lines exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. In this study, glycine transporter 1 knockdowns (GlyT1+/−) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR−/−) exhibit NMDAR hypofunction. GlyT1+/− mice displayed hastened extinction of conditioned place preference (CPP) and robust cocaine-induced reinstatement. SR−/− mice appeared to immediately “forget” the learned preference, because they did not exhibit cocaine-induced reinstatement. Treatment of GlyT1+/− mice with gavestinel, a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately “forget” the learned preference. Treatment of SR−/− mice with d-serine caused them to avoid the cocaine-paired side of the chamber during extinction. These results suggest drugs that activate the NMDAR GMS could be an effective treatment for cocaine abuse.
See article at J Pharmacol Exp Ther 2015, 353:465–470.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics