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bioRxiv · 10.1101/2025.02.14.638324

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

Montemarano, A.·Fox, L. D.·Alkhaleel, F. A.·Ostman, A. E.·Sohail, H.·Pandey, S.·Fox, M. E.
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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 adaptations that contribute to negative affect during fentanyl abstinence, but whether these neuroadaptations also promote fentanyl relapse is unclear. Here, we obtained Drd1-cre120Mxu mice to investigate D1-dependent mechanisms of fentanyl relapse. We serendipitously discovered this mouse line is resistant to fentanyl seeking, despite similar intravenous fentanyl self-administration, and greater fentanyl-induced locomotion, compared to wildtype counterparts. In drug naive mice, we found Drd1-cre120Mxu mice have elevated D1 receptor expression in NAc, alongside increased expression of MSN marker genes Chrm4 and Penk. We show Drd1-cre120Mxu mice have increased sensitivity to the D1 receptor agonist SKF-38393, and exhibit divergent expression of MSN markers, opioid receptors, glutamate receptor subunits, and TrkB after fentanyl self-administration that may underly blunted fentanyl seeking. Finally, we show fentanyl-related behavior is unaltered by chemogenetic manipulation of D1-MSNs in Drd1-cre120Mxu mice. Conversely, chemogenetic stimulation of 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.

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Montemarano, A., Fox, L. D., Alkhaleel, F. A., Ostman, A. E., Sohail, H., Pandey, S., Fox, M. E.. 2025-02-19. A Drd1-cre mouse line with nucleus accumbens gene dysregulation exhibits blunted fentanyl seeking. https://doi.org/10.1101/2025.02.14.638324

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