Striatal Mu-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

Wang, W.; Xie, X.; Zhuang, X.; Huang, Y.; Tan, T.; Gangal, H.; Huang, Z.; Purvines, W.; Wang, X.; Stefanov, A.; Chen, R.; Yu, E.; Hook, M.; Darcq, E.; Wang, J.

doi:10.1101/2022.05.23.493082

bioRxiv · 10.1101/2022.05.23.493082

Striatal Mu-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

Wang, W.·Xie, X.·Zhuang, X.·Huang, Y.·Tan, T.·Gangal, H.·Huang, Z.·Purvines, W.·Wang, X.·Stefanov, A.·Chen, R.·Yu, E.·Hook, M.·Darcq, E.·Wang, J.

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Abstract

Withdrawal 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 {micro}-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. HighlightsO_LIRepeated administration of morphine potentiates IPSCdMSN{lozenge}GPh neurotransmission. C_LIO_LIRepeated administration of fentanyl potentiates IPSCdMSN{lozenge}SNc neurotransmission. C_LIO_LIFentanyl withdrawal induces negative emotional states, which drive relapse. C_LI

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Wang, W., Xie, X., Zhuang, X., Huang, Y., Tan, T., Gangal, H., Huang, Z., Purvines, W., Wang, X., Stefanov, A., Chen, R., Yu, E., Hook, M., Darcq, E., Wang, J.. 2022-05-25. Striatal Mu-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect. https://doi.org/10.1101/2022.05.23.493082

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