# Activation of Insula‐Accumbal Projection Neurons Is Required for Relapse‐Like Behaviour Following Opioid Self‐Administration

## TL;DR

This study shows that a specific brain circuit involving the insular cortex and nucleus accumbens is crucial for opioid-seeking behavior and relapse in mice.

## Contribution

The study identifies a specific insula-to-accumbens projection that controls opioid-seeking behavior, offering new insights into opioid use disorder.

## Key findings

- Optogenetic inhibition of aIC➔NAcc terminals suppresses context-associated opioid seeking in mice.
- The same inhibition also reduces cued opioid seeking after extinction training.
- Sucrose seeking remains unaffected by the inhibition of aIC➔NAcc terminals.

## Abstract

The insular cortex (IC) is known to underlie drug seeking and relapse for multiple drug classes, yet the precise role the IC plays in opioid use disorder (OUD) remains unclear. In preclinical models of OUD, inhibition of the IC has produced conflicting results, such that in some cases the IC seems to promote opioid seeking whereas in others the IC seems to blunt opioid seeking. These results may be related to the heterogeneity of cortical output circuits, which can have opposing functions despite their relative proximity. Thus, here we examined the role of a specific IC output circuit, from the anterior IC (aIC) to the nucleus accumbens core (NAcc), for opioid seeking. We find in mice that following 14 days of heroin self‐administration and 3 days of forced abstinence, optogenetic inhibition of aIC➔NAcc terminals suppresses context‐associated opioid seeking. Furthermore, the same manipulation attenuates cued opioid seeking following extinction training. Importantly, we observed no effect of aIC➔NAcc terminal inhibition on sucrose seeking. Together, our results reveal that the IC selectively controls opioid seeking through a discrete population of NAcc projecting neurons, providing the first evidence for a projection‐specific role of IC circuitry in opioid seeking and relapse.

The aIC has been implicated in opioid‐related behaviours, but the function of output‐defined aIC projection neurons for opioid seeking remains unknown. Using optogenetics we find that inhibition of activity in aIC➔NAcc projection neurons prevents context‐related and cue‐induced heroin seeking, whereas sucrose seeking is unaffected. Our results reveal that the aIC controls opioid seeking through a discrete population of NAcc projecting neurons, providing the first evidence for a role of the aIC➔NAcc projection in opioid seeking and relapse.