mGlu 1 Activation Reverses Persistent Deficits in Prefrontal Cortex Inhibitory Transmission and Working Memory Induced by Adolescent Cocaine Exposure

The prefrontal cortex (PFC), a brain region central to cognitive processes such as working memory, and executive function, undergoes complex structural and functional maturation across adolescence, rendering it particularly vulnerable to disruption by external events. Exposure to psychostimulants, such as cocaine, during adolescence produces persistent changes in PFC structure and function which parallel cognitive deficits seen in adulthood. However, the mechanisms of how drug exposure during critical developmental periods alter PFC function and cognition performance in adulthood are not fully understood. Extensive evidence suggests that the balance between excitatory and inhibitory neurotransmission in the PFC plays a fundamental role in many cognitive processes. Furthermore, adolescent exposure to psychostimulants impairs GABA interneuron function and inhibitory transmission in the PFC in adulthood, suggesting that enhancing PFC inhibitory transmission may be a promising strategy to mitigate drug‐induced cognitive deficits observed later in life. Recently, we found that activation of the mGlu 1 subtype of metabotropic glutamate receptor increases PFC inhibitory transmission and working memory by selective excitation of somatostatin‐expressing GABA interneurons (SST‐INs), highlighting mGlu 1 as a novel target for restoring inhibitory transmission in the PFC and enhancing cognition. These findings lead us to hypothesize that repeated exposure to cocaine during a critical developmental period in adolescence disrupts inhibitory transmission in the PFC via SST‐INs and that this contributes to working memory impairments in adulthood. We further propose that selective activation of mGlu 1 with highly selective positive allosteric modulators (PAMs) will reverse cocaine‐induced physiological and behavioral deficits. Here, we leveraged transgenic mouse lines in combination with whole‐cell patch‐clamp electrophysiology, maze‐ and touchscreen‐based automated cognition testing. We found that repeated administration of cocaine during a critical adolescent period (PND 35‐42) significantly impaired PFC SST‐IN, but not parvalbumin‐expressing interneuron (PV‐IN), firing compared to saline‐treated mice. Additionally, adolescent cocaine exposure significantly decreased the frequency of spontaneous excitatory postsynaptic currents onto SST‐INs but not PV‐INs. In parallel, adolescent cocaine‐induced impairments in spatial working memory in adulthood. Importantly, these physiological and behavioral effects of adolescent cocaine exposure were reversed by selective mGlu 1 activation. Lastly, repeated amphetamine administration during the same adolescent critical period did not impair SST‐IN function or working memory in adulthood. In sum, these findings provide strong evidence that: 1) cocaine exposure during an adolescent critical period induces persistent and selective deficits in PFC SST‐IN function and spatial working memory in adulthood and 2) selective activation of mGlu 1 with PAMs represents a promising novel strategy for reversing cocaine‐induced cognitive impairments.