Distinct, learning-dependent neural mechanisms regulating cocaine and heroin seeking

Understanding the neural mechanisms that promote vs suppress drug seeking is critical to improving outcomes for individuals with substance use disorder. Considerable evidence implicates the anterior insular cortex and infralimbic cortex in promoting and suppressing drug seeking, respectively, for psychostimulants such as cocaine. However, the role of these brain regions in regulating opioid seeking has been comparatively understudied. To address this gap, we trained rats to press a lever to self-administer heroin. Then, to introduce a reason for rats to suppress their heroin seeking, we removed all consequences of a lever press, resulting in a decrease, or extinction, of lever pressing. Evidence indicates that inhibiting the infralimbic cortex or its projections to two downstream brain regions, the nucleus accumbens shell or amygdala, impairs cocaine extinction learning. However, the present work found no effect of these same manipulations on the extinction of heroin seeking. Evidence also indicates that anterior insular cortex inhibition decreases cued reinstatement (relapse) of cocaine seeking, yet the present work found that this manipulation increased cued heroin seeking only after extinction learning. Together, these results indicate that distinct, learning-dependent mechanisms regulate cocaine and heroin seeking.

A broader question in the field is whether extinction-reinstatement procedures in rats sufficiently recapitulate the in-the-moment competing motivations experienced by individuals with substance use disorder. To this end, we developed a novel competition task wherein distinct stimuli signaled whether a lever press would produce cocaine, a footshock, or both (when presented simultaneously). The present behavioral results demonstrate the viability of this approach.