A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking

In substance use disorders, negative affect associated with drug withdrawal can elicit strong drug craving and promote relapse. One brain region implicated in those processes is the rostral agranular insular cortex (RAIC), although precisely how this region encodes negative affect associated with drug seeking is unknown. Here, a preclinical model was used where RAIC activity was examined in male Sprague Dawley rats during intraoral infusions of a sweet (saccharin) paired with impending but delayed access to cocaine self-administration, and for comparative purposes, during the sweet predicting saline self-administration or injection of lithium chloride (LiCl), or during intraoral infusions of a bitter taste (quinine). Consistent with previous work, cocaine-paired saccharin, LiCl-paired saccharin, and quinine all elicited aversive taste reactivity. However, the aversive taste reactivity elicited by the cocaine-paired tastant was qualitatively different from that evoked by the other two agents. Furthermore, differences in taste reactivity were reflected in RAIC cell firing, where distinct shifts in neural signaling were observed specifically after cocaine but not LiCl conditioning. Notably, low motivation for cocaine (indicated by low loading and slower latencies to lever press) was correlated with this shift in RAIC signaling, but aversive (gaping) responses were not. Collectively, these findings indicate that cocaine-paired tastants elicit unique aspects of aversive behaviors that differ from traditional conditioned taste aversion (LiCl) or quinine and that the RAIC plays a role in modulating drug-seeking behaviors driven by drug-induced dysphoria (craving), but not negative affect per se.