The mesolimbic reward pathway is necessary for disruptions in cocaine-seeking behavior following mediated devaluation.

We developed an approach to disrupt cocaine-seeking behaviors using mediated devaluation. Male rats underwent cocaine self-administration training in which active lever responses led to cocaine infusions and the presentation of a tone-light conditioned stimulus (CS). Subsequently, during mediated devaluation rats received non-contingent presentations of the cocaine-associated CS in a second distinct context, which led to the cue-evoked retrieval of associated memories. This was immediately followed by an intraperitoneal injection of lithium chloride (LiCl) and served to pair the memory of cocaine reward with gastric malaise. Consequently, this led to a substantial reduction in cocaine-seeking behavior during extinction training, relative to rats that received CS-saline or LiCl alone during mediated devaluation. Cue- and cocaine-evoked reinstatement testing indicated that the manipulations did not devalue the CS or the reinforcing properties of cocaine. A separate cohort of rats received a dual-viral chemogenetic strategy that permitted circuit-specific inactivation of midbrain ventral tegmental area (VTA) cells projecting to the nucleus accumbens (NAc). Inactivation of VTA→NAc circuitry during mediated devaluation prevented the subsequent reduction of cocaine-seeking behavior during extinction training. Overall, these findings suggest that intact mesolimbic signaling is required to enable disruptions in cocaine-seeking behavior following mediated devaluation.