Insula dynorphin and kappa opioid receptor systems regulate alcohol drinking in a sex-specific manner in mice

Abstract

Alcohol use disorder is complex and multi-faceted, involving the engagement of multiple signaling systems across numerous brain regions to drive pathological behavior. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit elements on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR systems in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact their sucrose intake. In male mice, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA only. Alcohol consumption as not affected by insula KOR knockout. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest that there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR circuit elements.

Escalation of alcohol intake is associated with regionally decreased insular cortex activity but not associated with changes in taste quality

“…Furthermore, deletion of dynorphin within IC blocks escalated EtOH intake in mice (Pina et al, 2021). Interestingly, the number of aversive responses to EtOH was negatively correlated with the number of FLI+ cells within the anterior IC, although this difference did not quite reach statistical significance.…”

“…Opioid signaling within this area of IC increases the positively hedonic “liking” response elicited by intraorally delivered sucrose solutions (Castro and Berridge, 2017) further demonstrating that neural adaptations within this subregion of IC may be critical for driving enhancements of hedonic responding to orally delivered stimuli. Furthermore, deletion of dynorphin within IC blocks escalated EtOH intake in mice (Pina et al, 2021). Interestingly, the number of aversive responses to EtOH was negatively correlated with the number of FLI+ cells within the anterior IC, although this difference did not quite reach statistical significance.…”

Escalation of alcohol intake is associated with regionally decreased insular cortex activity but not changes in taste quality

“…Opioid signaling within this area of IC increases the positively hedonic “liking” response elicited by intraorally delivered sucrose solutions (Castro & Berridge, 2017) further demonstrating that neural adaptations within this subregion of IC may be critical for driving enhancements of hedonic responding to orally delivered stimuli. Furthermore, deletion of dynorphin within IC blocks escalated EtOH intake in mice (Pina et al, 2021). Interestingly, the number of aversive responses to EtOH was negatively correlated with the number of FLI+ cells within the anterior IC, although this difference did not quite reach statistical significance.…”

Sexual dimorphism of insular cortex function in persistent alcohol drinking despite aversion in mice

“…The insular cortex (or insula), is strongly involved in drug addiction (32)(33)(34), including AUD (35)(36)(37). Indeed, human functional imaging studies have demonstrated that alcohol cues trigger greater activity responses in the insula, in alcohol dependent subjects (38,39).…”