Metabotropic mGlu1Receptor Regulation of Cortical Inhibition and Cognitive Function: Implications in Adolescent Cocaine Exposure

Abstract ID 95290 Poster Board 322 Aim: Exposure to psychostimulants, such as cocaine, during adolescence produces persistent changes in the prefrontal cortex (PFC) which parallel cognitive deficits seen in adulthood. Further, adolescent exposure to psychostimulants impairs inhibitory transmission in the PFC in adulthood, suggesting that enhancing PFC inhibitory transmission may be a promising strategy to reverse drug-induced cognitive deficits. Activation of the mGlu1 subtype of metabotropic glutamate receptor increases inhibitory transmission in the PFC and working memory by selective excitation of somatostatin-expressing GABA interneurons (SST-INs). Therefore, we hypothesize that repeated exposure to cocaine during a critical developmental period in adolescence disrupts PFC inhibition via SST-INs and drives working memory impairments in adulthood which can be mitigated by activation of mGlu1. Methods: Male and female SST- and PV-Ai9 tdTomato mice were injected once daily with cocaine (20 mg/kg, i.p.) for 7 days (postnatal day 35-42). Whole-cell patch-clamp electrophysiological recordings from interneuron populations within the PFC were conducted between 10-12 weeks of age. Additionally, touchscreen-based automated cognition testing was used to determine working memory performance in adult mice. Novel mGlu1 positive allosteric modulators (PAMs) were leveraged in behavioral and electrophysiology studies to determine their procognitive efficacy and mechanism of action within the PFC. Results: We found that repeated administration of cocaine during a critical adolescent period impaired PFC SST-IN, but not parvalbumin-expressing interneuron (PV-IN), firing compared to saline-treated mice. Adolescent cocaine exposure significantly decreased the frequency of spontaneous excitatory postsynaptic currents onto SST-INs but not PV-INs. These findings were paralleled by adolescent cocaine-induced impairments in spatial working memory in adulthood. Importantly, these physiological and behavioral effects of adolescent cocaine exposure were reversed by selective mGlu1 activation. Lastly, repeated amphetamine administration during the same adolescent critical period did not result in impaired SST-IN function or spatial working memory in adulthood. Conclusions: These studies show that: 1) cocaine, but not amphetamine, exposure during an adolescent critical period induces persistent and selective deficits in PFC SST-IN function and cognition in adulthood and 2) selective activation of mGlu1 with PAMs represents a novel strategy for reversing cocaine-induced cognitive impairments. This work is supported by MH119673, NS031373, MH062646, MH073676, MH065215