Striatal -Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect Institutional Repository Document uri icon

abstract

  • SUMMARYWithdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which drives relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain high levels of -opioid receptors (MORs). It remains unclear how chronic opioid exposure affects these MOR-expressing dMSNs and their striatopallidal and striatonigral outputs to induce negative emotions and relapse. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, repeated administrations of a MOR agonist (morphine or fentanyl) potentiated this GABAergic transmission. We also discovered that intravenous self-administration of fentanyl enhanced GABAergic striatonigral transmission and reduced the firing activity of midbrain dopaminergic neurons. Importantly, fentanyl withdrawal caused depression-like behaviors and promoted the reinstatement of fentanyl-seeking behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, promoting negative emotions and leading to relapse.HighlightsRepeated administration of morphine potentiates IPSCdMSNGPhneurotransmission.Repeated administration of fentanyl potentiates IPSCdMSNSNcneurotransmission.Fentanyl withdrawal induces negative emotional states, which drive relapse.

altmetric score

  • 1.85

author list (cited authors)

  • Wang, W., Xie, X., Zhuang, X., Huang, Y., Tan, T., Gangal, H., ... Wang, J.

citation count

  • 1

complete list of authors

  • Wang, Wei||Xie, Xueyi||Zhuang, Xiaowen||Huang, Yufei||Tan, Tao||Gangal, Himanshu||Huang, Zhenbo||Purvines, William||Wang, Xuehua||Stefanov, Alexander||Chen, Ruifeng||Yu, Emily||Hook, Michelle||Huang, Yun||Darcq, Emmanuel||Wang, Jun

Book Title

  • bioRxiv

publication date

  • May 2022