A glutamatergic insular-striatal projection regulates the reinstatement of cue-associated morphine-seeking behavior in mice.

Recently, the insular cortex (IC) was identified as part of the neuronal circuit responsible for the reward expectations in cue-triggered behaviours. Moreover, there are evidences that connections between the IC and the ventral striatum, particularly with the nucleus accumbens (NAc), may mediate the retrieval and performance of actions based on incentive memory. However, the precise role of the IC-NAc connections in cue-related drug-seeking behaviour remains unclear. We used the morphine-induced conditioned place preference (CPP) paradigm to assess the formation and relapse of cue-related drug-seeking. cFos immunostaining was used to determine the activation of the brain regions. Chemogenetic and optogenetic methods were used to manipulate the activity of IC-to-NAc projection neurons. The result showed that neurons in IC and NAc core but not NAc shell were activated following cue-induced morphine-seeking behaviour. Negligible effect of inhibition of IC-to-NAc core projection (IC→NAc core) on morphine CPP expression, whereas chemogenetic inactivation of this projection potently blocked the reinstatement of expressed morphine CPP. Furthermore, optogenetic inhibition of glutamatergic IC→NAc core inputs significant suppressed the CPP reinstatement without significant effect on CPP expression. We demonstrated here, for the first time, that IC→NAc core glutamatergic projection is required for the reinstatement of cue-associated drug seeking behaviour in mice. The present study provide insights into modulations of relapse of cue-associated drug-seeking behaviour following repeated overexposure to opioids in humans.