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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Abstract The synthetic opioid fentanyl remains abundant in the illicit drug supply, contributing to tens of thousands overdose deaths every year. Despite this, neurobiological effects use remain largely understudied. nucleus accumbens (NAc) is a central locus promoting persistent and relapse, dependent on activity dopamine D1 receptors. NAc receptor-expressing medium spiny neurons (D1-MSNs) undergo molecular physiological adaptations that contribute negative affect during abstinence, but whether these neuroadaptations also promote relapse unclear. Here, we obtained Drd1-cre 120Mxu mice investigate D1-dependent mechanisms relapse. We serendipitously discovered this mouse line resistant seeking, despite similar intravenous self-administration, greater fentanyl-induced locomotion, compared wildtype counterparts. In naïve mice, found have elevated receptor expression NAc, alongside increased MSN marker genes Chrm4 Penk . show sensitivity agonist SKF-38393, exhibit divergent markers, receptors, glutamate subunits, TrkB after self-administration may underly blunted seeking. Finally, fentanyl-related behavior unaltered by chemogenetic manipulation D1-MSNs mice. Conversely, stimulation putative recapitulated seeking supporting role for aberrant D1-MSN signaling behavior. Together, our data uncover alterations gene function with implications susceptibility resistance developing disorder.

Язык: Английский

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

Neuropsychopharmacology, Год журнала: 2025, Номер unknown

Опубликована: Май 2, 2025

Abstract The synthetic opioid fentanyl remains abundant in the illicit drug supply, contributing to tens of thousands overdose deaths every year. Despite this, neurobiological effects use remain largely understudied. nucleus accumbens (NAc) is a central locus promoting persistent and relapse, dependent on activity dopamine D1 receptors. NAc receptor-expressing medium spiny neurons (D1-MSNs) undergo molecular physiological neuroadaptations response chronic that may promote relapse. Here, we obtained Drd1-cre 120Mxu mice investigate D1-dependent mechanisms We serendipitously discovered this mouse line has reduced seeking, despite similar intravenous self-administration, sucrose self-administration greater fentanyl-induced locomotion compared wildtype counterparts. found drug-naïve have elevated receptor expression increased sensitivity agonist SKF-38393. After exhibit divergent MSN markers, receptors, glutamate subunits, TrkB which underly their blunted seeking. Finally, show fentanyl-related behavior unaltered by chemogenetic manipulation core D1-MSNs mice. Conversely, stimulation ventral mesencephalon-projecting MSNs (putative D1-MSNs) recapitulated seeking mice, supporting role for aberrant D1-MSN signaling behavior. Together, our data uncover alterations gene function with implications susceptibility resistance developing disorder.

Язык: Английский