Dopamine inhibits GABAA currents in ventral tegmental area dopamine neurons via activation of presynaptic G-protein coupled inwardly-rectifying potassium channels

A. Michaeli, R. Yaka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Dopamine (DA) neurons in the ventral tegmental area (VTA) constitute the origin of major dopaminergic neural pathways associated with essential functions including reward, motivation and cognition. Hence, regulation of VTA DA neurons' excitability is of important significance. Like other neurons, the activity level of VTA DA neurons is considerably determined by excitatory and inhibitory synaptic inputs. Here we show that DA itself, the most available modulator in the VTA, causes an inhibition of GABA receptor type A (GABAAR)-mediated evoked-IPSC (eIPSC) recorded from rat VTA DA neurons. The DA-induced inhibition was accomplished by activation of DA receptors, known to inhibit adenylyl cyclase activity (D2-like receptors), and was absent when these receptors were blocked. Moreover, blocking of either GABA receptor type B (GABABR) or G-protein coupled inwardly-rectifying potassium (GIRK) channels was also found to effectively prevent the DA-induced inhibition of GABAAR eIPSC. In addition, we found that DA changes the values of both paired-pulse ratio (PPR) and coefficient of variation (CV) of GABAAR eIPSC amplitude, similar to the changes obtained by lowering the extracellular calcium concentration. Taken together, we propose that activation of D2-like receptors and GABABR in the VTA enhances presynaptic GIRK channels activity, which in turn leads to reduced GABA release. The consequence of reduced GABA release on VTA DA neurons may contribute to their increased activity. Accordingly, a novel potential regulatory form of VTA DA neurons' excitability, which involves presynaptic potassium channels, is proposed.

Original languageAmerican English
Pages (from-to)1159-1169
Number of pages11
JournalNeuroscience
Volume165
Issue number4
DOIs
StatePublished - 17 Feb 2010

Bibliographical note

Funding Information:
This research was supported by the Israel Science Foundation (grant No. 292/05 ) and the National Institute for Psychobiology in Israel founded by the Charles E. Smith family. R. Yaka is affiliated with the David R. Bloom Center for Pharmacy and the Brettler Center for Research in Molecular Pharmacology and Therapeutics, School of Pharmacy, The Hebrew University of Jerusalem.

Keywords

  • GABA receptor
  • GIRK
  • disinhibition
  • dopamine
  • psychostimulants
  • reward circuit

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