Incubation of cocaine craving is associated with reduced context-induced Fos expression in parvalbumin interneurons in the nucleus accumbens core of male rats.

Substance use disorder develops in a subset of individuals after repeated drug exposure and is characterized by escalating intake and loss of control over use. Rodent self-administration protocols with varying drug access durations are used to study controlled and compulsive drug use and its neurobiology. Drug-associated stimuli are major triggers for relapse. In humans, the craving response elicited by these stimuli progressively increases during abstinence, contributing to high relapse rates. In animals, an analogous process is observed, termed incubation of cocaine craving, which is characterized by a progressive increase in context-induced drug-seeking behavior over the course of abstinence. Associative learning between environmental stimuli and drug use is encoded by neuronal ensembles reactivated by drug-related stimuli, driving drug seeking. In the NAcc, these ensembles regulate cue-driven behaviors, while PV interneurons provide inhibitory control over network activity. We examined overall NAcc and PV-specific recruitment by measuring Fos expression in response to the cocaine-associated context after restricted or extended access self-administration and assessed whether this recruitment is modulated by forced abstinence. The magnitude of context-induced Fos expression in the NAcc core and shell before abstinence was influenced by the amount of cocaine intake during training, with greater expression in extended access rats. NAcc core and shell Fos expression increased after 30 days of abstinence in both groups but was consistently higher in extended access rats. PV Fos expression decreased in extended access rats following forced abstinence. These findings suggest that the Incubated cocaine craving alters NAcc and PV interneuron recruitment.