Cocaine dysregulates dynorphin modulation of inhibitory neurotransmission in the ventral pallidum in a cell-type-specific manner

Kineret Inbar, Liran A. Levi, Nimrod Bernat, Tal Odesser, Dorrit Inbar, Yonatan M. Kupchik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VPGABA neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VPGABA neurons, dynorphin surprisingly potentiated the inhibitory input on VPvGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VPGABA and VPvGluT2 neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VPGABA and VPvGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine.

Original languageAmerican English
Pages (from-to)1321-1331
Number of pages11
JournalJournal of Neuroscience
Volume40
Issue number6
DOIs
StatePublished - 5 Feb 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 the authors.

Keywords

  • Cocaine
  • Dynorphin
  • Electrophysiology
  • GABA
  • VGluT2 neurons
  • Ventral pallidum

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