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

Abstract

<b>Abstract ID 13858</b> <b>Poster Board 570</b> <b>Aim:</b> 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. <b>Methods:</b> Male and female mice were injected once daily with cocaine (20 mg/kg, i.p.) for 7 days (PND 35-42). Behavioral and electrophysiological testing was conducted between 10-12 weeks of age. mGlu₁ positive allosteric modulators (PAMs), ssT- and PV-Ai9 tdTomato mice, whole-cell patch-clamp electrophysiology, maze- and touchscreen-based automated cognition testing. <b>Results:</b> 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. <b>Conclusions:</b> 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