Perirhinal cortex to the nucleus accumbens circuit in novelty salience following methamphetamine self-administration.

Methamphetamine (meth) use disorder is part of an overarching use disorder that encompasses continued drug seeking and an increased risk of returning to drug use following periods of abstaining. Chronic meth use results in drug-induced cortical plasticity in the perirhinal cortex (PRC) that mediates responses to novelty. PRH projection targets are numerous and include the nucleus accumbens core (NAc). Whereas the PRH-prefrontal cortex is involved in object recognition; we propose that the PRH-NAc is involved in novelty salience. Rats underwent short-access (ShA, 1 hr) or long-access (LgA, 6 hr) meth self-administration (SA). We then used a dual viral strategy to inhibit or activate PRH-NAc during a novel cue test in which rats were presented with meth-associated and novel levers. Response patterns on these levers differ depending on the meth access protocol: ShA meth SA results in equal responding on both novel- and meth-associated levers, whereas LgA meth results in perseverative responding on the meth-associated lever. Inactivation of the PRH-NAc increased responding on the meth lever relative to the novel lever, resulting in a LgA behavioral phenotype. In contrast, activation in LgA rats was without a behavioral effect. We also report that male LgA sucrose SA animals perseverated on the novel lever rather than the meth-associated lever, which contrast their meth SA counter parts and female specific patterns of behavior. These data open a new line of interest in the role of the PRH-NAc circuit in novelty salience through identification of the behavioral relevance of this circuit.