Chemogenetic modulation of the prelimbic cortex to the nucleus accumbens core pathway reduces cocaine-induced increase of risk preference

Decision-making impairments are a core symptom of several psychiatric disorders, including gambling and substance use disorders (SUD). These disorders frequently co-occur, suggesting shared neurobiological mechanisms underlying dysfunctional decision-making. We previously demonstrated that chronic cocaine exposure increases risk preference in a rat gambling task (rGT). Given that the prelimbic cortex (PrL) to the nucleus accumbens (NAc) core pathway plays a crucial role in regulating risk-based decision-making, we further explored how chemogenetic modulation of this pathway alters cocaine-induced increase in risky decision-making in the rGT. Notably, activation of Gi, but not Gq, designer receptors exclusively activated by designer drugs (DREADD) in the PrL attenuated the cocaine-induced increase of risk preference in risk-averse rats, while simultaneously reducing cocaine-induced attentional deficits measured by task omissions. Subsequent molecular analyses revealed that cocaine significantly induced changes in the expression levels of calcium channel alpha 1 C subunit (CaV1.2) and in the ratio of phosphorylation at serine 97 of total dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32) in the PrL region of these rats, which returned to basal levels with concurrent Gi-DREADD activation. No significant behavioral or molecular changes were observed in risk-seeking rats. These results suggest that modulating the PrL-NAc core pathway can selectively control risk-based decision-making behavior and attentional processes affected by cocaine exposure, offering therapeutic potential for addressing decision-making impairments in dual diagnoses of gambling and SUD.