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Rationale: Cocaine addiction is marked by high relapse rates, often triggered by drug-associated cues in the environment. These can be conditioned stimuli (CSs), which occur after drug intake and signal drug delivery, and discriminative stimuli (DSs), which signal that seeking responses will produce drug, before any such responses have been initiated (i.e., response-independently). While projections from the infralimbic cortex (IL) to the nucleus accumbens (NAc) shell are known to regulate CS-mediated cocaine relapse, their role in DS-triggered relapse is not known.

Objectives: We examined how activating IL?NAc shell projections influences relapse induced by response-independent DS and CS presentation during abstinence from intermittent cocaine self-administration.

Methods: Female Sprague-Dawley rats received viral-mediated gene expression of excitatory designer receptors exclusively activated by designer drugs in the IL. Rats then self-administered cocaine during intermittent-access sessions (5-min cocaine ON/25-min cocaine OFF, 4 h/day). A discrete light (DS+) signalled drug-available periods. A different light (DS-) signalled drug non-availability. During each DS + period, cocaine infusions were paired with a compound light-tone (CS+). Four weeks later, rats were tested for cue-induced cocaine seeking following response-independent presentation of DS+, CS+ or DS+/CS+ combined. Prior to testing, rats received intra-NAc shell aCSF or clozapine N-oxide to activate IL terminals.

Results: The DS+ alone and DS+/CS+ combined triggered greater cocaine seeking than did the CS+. Activation of IL?NAc shell projections suppressed relapse behaviour in DS+ and DS+/CS+ conditions.

Conclusions: These findings highlight the distinct influence of DSs on relapse and support the IL?NAc shell circuit as a promising target for relapse prevention.