RT Journal Article
SR Electronic
T1 Delineation of insula dynorphin and kappa opioid receptor circuit elements in alcohol consumption
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.09.467893
DO 10.1101/2021.11.09.467893
A1 Melanie M. Pina
A1 Dipanwita Pati
A1 Sofia Neira
A1 Christina M. Stanhope
A1 Alexandra A. Mahoney
A1 Shannon D’Ambrosio
A1 Thomas L. Kash
A1 Montserrat Navarro
YR 2021
UL http://biorxiv.org/content/early/2021/11/10/2021.11.09.467893.1.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.