Dorsolateral striatum dopamine-dependent cocaine seeking is resistant to pavlovian cue extinction in male and female rats

Cue exposure therapy (CET) reduces craving induced by drug-associated cues in individuals with substance use disorders. A preclinical model of CET, cue extinction, similarly reduces cue-induced cocaine seeking in rodent self-administration models; however, those models may not capture the habitual or compulsive aspects of drug use. Thus, the effectiveness of cue extinction was tested in male and female rats trained to self-administer cocaine using second-order (SO) or fixed-ratio (FR) schedules of reinforcement to facilitate dorsolateral striatum (DLS) dopamine-dependent or -independent response strategies, respectively. Cue extinction significantly reduced drug seeking in FR-trained rats, replicating prior results, but was ineffective in SO-trained rats. SO-trained rats also showed increased indices of glutamate signaling in the DLS relative to FR-trained rats, despite comparable levels of cocaine intake. Furthermore, in SO-trained rats, antagonism of AMPA receptors in the DLS rescued the efficacy of cue extinction to reduce drug seeking. Finally, the effectiveness of cue extinction was also revealed in SO-trained rats when they were taught to perform a new, non-habitual response for cocaine cue presentation. Overall, our findings indicate that habit-like drug seeking leads to plasticity in the DLS and behavior that is resistant to cue extinction, but that the effects of cue extinction are restored when DLS glutamatergic signaling is blocked. These results have implications for the effectiveness of clinical cue exposure therapy.