Acute cocaine exposure weakens GABAB receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area

Devinder Arora, Matthew Hearing, Desirae M. Haluk, Kelsey Mirkovic, Ana Fajardo-Serrano, Martin W. Wessendorf, Masahiko Watanabe, Rafael Luján, Kevin Wickman

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41 Scopus citations


Enhanced glutamatergic neurotransmission in dopamine (DA) neurons of the ventral tegmental area (VTA), triggered by a single cocaine injection, represents an early adaptation linked to the more enduring effects of abused drugs that characterize addiction. Here, we examined the impact of in vivo cocaine exposure on metabotropic inhibitory signaling involving G-protein-gated inwardly rectifyingK+ (Girk) channels in VTA DA neurons. Somatodendritic Girk currents evoked by the GABAB receptor (GABABR) agonist baclofen were diminished in a dose-dependent manner in mice given a single cocaine injection. This adaptation persisted for 3-4 d, was specific for DA neurons of the VTA, and occurred in parallel with an increase in spontaneous glutamatergic neurotransmission. No additional suppression of GABABR-Girk signaling was observed following repeated cocaine administration. While total Girk2 and GABABR1 mRNA and protein levels were unaltered by cocaine exposure in VTA DA neurons, the cocaine-induced decrease in GABABR-Girk signaling correlated with a reduction in Girk2-containing channels at the plasma membrane in VTA DA neurons. Systemic pretreatment with sulpiride, but not SCH23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), prevented the cocaine-induced suppression of GABABR-Girk signaling, implicating DGABA2/3 DA receptor activation in this adaptation. The acute cocaine-induced weakening of somatodendritic Girk signaling complements the previously demonstrated cocaine-induced strengthening of glutamatergic neurotransmission, likely contributing to enhanced output of VTA DA neurons during the early stages of addiction.

Original languageEnglish (US)
Pages (from-to)12251-12257
Number of pages7
JournalJournal of Neuroscience
Issue number34
StatePublished - Aug 24 2011

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