The role of the prelimbic cortex to nucleus accumbens core projection in the reinstatement of cocaine-seeking after cocaine-alcohol polysubstance use.

Abstract

Cocaine use disorder (CUD) is a chronic, relapsing disorder that affects over one million people in the United States. Rodent models of cocaine use disorder are critical for identifying neuroadaptations driving cocaine-seeking. However, such models rarely consider polysubstance use (PSU), despite the majority of cocaine users reporting use of more than one drug. Use of a rodent model of sequential cocaine and alcohol PSU finds that, unlike after cocaine self-administration alone, reinstatement of cocaine-seeking is not accompanied by glutamate efflux in the nucleus accumbens core (NAc). Here we use chemogenetic strategies to explore whether activity in prelimbic (PL) cortical neurons that project to the NAc is necessary for cue-primed reinstatement of cocaine-seeking in this sequential model of cocaine-alcohol PSU. Rats underwent intravenous self-administration of cocaine followed by access to either water alone or water and alcohol (20% v/v). Following instrumental extinction, rats received a cue-primed reinstatement test following CNO (3 mg/kg) to stimulate (Gq-coupled DREADD) or inhibit (Gi-coupled DREADD) the PL-NAc projection. DREADD-mediated inhibition of this projection failed to prevent cue-primed reinstatement of cocaine-seeking in the PSU condition but did so in the cocaine-only condition. DREADD-mediated stimulation of the same neuronal subpopulation failed to increase cue-primed reinstatement and cocaine-induced locomotion, suggesting potential limits to the influence of nucleus accumbens core-projecting prelimbic neurons over cocaine seeking and locomotion. These findings indicate that sequential cocaine-alcohol PSU changes the neurocircuitry of relapse and may necessitate new approaches for treating cocaine use with an alcohol co-use component.