Sex-dependent modulation of behavioral allocation via ventral tegmental area-nucleus accumbens shell circuitry

Diagnostic criteria for substance use disorder, cocaine type (i.e., cocaine use disorder), outlined in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, imply that the disorder arises, at least in part, from the maladaptive allocation of behavior to drug use. To date, however, the neural circuits involved in the allocation of behavior have not been systematically evaluated. Herein, a chemogenetics approach (i.e., designer receptors exclusively activated by designer drugs (DREADDs)) was utilized in combination with a concurrent choice self-administration experimental paradigm to evaluate the role of the mesolimbic neurocircuit in the allocation of behavior. Pharmacological activation of hM3D(G_q) DREADDs in neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (AcbSh) induced a sex-dependent shift in the allocation of behavior in rodents transduced with DREADDs. Specifically, male DREADDs animals exhibited a robust increase in responding for a natural (i.e., sucrose) reward following pharmacological activation of the VTA-AcbSh circuit; female DREADDs rodents, in sharp contrast, displayed a prominent decrease in drug-reinforced (i.e., cocaine) responding. The sequential activation of hM3D(G_q) and KORD DREADDs within the same neuronal population validated the role of the VTA-AcbSh circuit in reinforced responding for concurrently available natural and drug rewards. Collectively, the VTA-AcbSh circuit is fundamentally involved in behavioral allocation affording a key target for the development of novel pharmacotherapies.