# A Drd1-cre mouse line with nucleus accumbens gene dysregulation exhibits blunted fentanyl seeking

## TL;DR

A specific mouse line shows reduced fentanyl-seeking behavior, revealing changes in brain gene activity that may explain resistance to opioid use disorder.

## Contribution

Identifies a Drd1-cre mouse line with altered nucleus accumbens gene expression and blunted fentanyl seeking, suggesting new mechanisms for opioid relapse.

## Key findings

- Drd1-cre120Mxu mice show reduced fentanyl seeking despite similar initial drug and sucrose self-administration.
- Altered NAc gene expression in these mice includes opioid receptors, glutamate subunits, and TrkB.
- Chemogenetic stimulation of NAc core MSNs in wildtype mice mimics the blunted fentanyl seeking of Drd1-cre120Mxu mice.

## Abstract

The synthetic opioid fentanyl remains abundant in the illicit drug supply, contributing to tens of thousands of overdose deaths every year. Despite this, the neurobiological effects of fentanyl use remain largely understudied. The nucleus accumbens (NAc) is a central locus promoting persistent drug use and relapse, largely dependent on activity of dopamine D1 receptors. NAc D1 receptor-expressing medium spiny neurons (D1-MSNs) undergo molecular and physiological neuroadaptations in response to chronic fentanyl that may promote relapse. Here, we obtained Drd1-cre120Mxu mice to investigate D1-dependent mechanisms of fentanyl relapse. We serendipitously discovered this mouse line has reduced fentanyl seeking, despite similar intravenous fentanyl self-administration, similar sucrose self-administration and seeking, and greater fentanyl-induced locomotion compared to wildtype counterparts. We found drug-naïve Drd1-cre120Mxu mice have elevated D1 receptor expression in NAc and increased sensitivity to the D1 receptor agonist SKF-38393. After fentanyl self-administration, Drd1-cre120Mxu mice exhibit divergent expression of MSN markers, opioid receptors, glutamate receptor subunits, and TrkB which may underly their blunted fentanyl seeking. Finally, we show fentanyl-related behavior is unaltered by chemogenetic manipulation of NAc core D1-MSNs in Drd1-cre120Mxu mice. Conversely, chemogenetic stimulation of ventral mesencephalon-projecting NAc core MSNs (putative D1-MSNs) in wildtype mice recapitulated the blunted fentanyl seeking of Drd1-cre120Mxu mice, supporting a role for aberrant D1-MSN signaling in this behavior. Together, our data uncover alterations in NAc gene expression and function with implications for susceptibility and resistance to developing fentanyl use disorder.