D2 dopamine receptor activation facilitates endocannabinoid- mediated long-term synaptic depression of GABAergic synaptic transmission in midbrain dopamine neurons via cAMP-protein kinase A signaling

Bin Pan, Cecilia J. Hillard, Qing Song Liu

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Endocannabinoid (eCB) signaling mediates short-term and long-term synaptic depression (LTD) in many brain areas. In the ventral tegmental area (VTA) and striatum, D2 dopamine receptors cooperate with group I metabotropic glutamate receptors (mGluRs) to induce eCB-mediated LTD of glutamatergic excitatory and GABAergic inhibitory (I-LTD) synaptic transmission. Because D2 receptors and group I mGluR agonists are capable of inducing the release of eCBs, the predominant hypothesis is that the cooperation between these receptors to induce eCB-mediated synaptic depression results from the combined activation of type I cannabinoid (CB1) receptors by the eCBs. By determining the downstream effectors for D2 receptor and group I mGluR activation in VTA dopamine neurons, we show that group I mGluR activation contributes to I-LTD induction by enhancing eCB release and CB 1 receptor activation. However, D2 receptor activation does not enhance CB1 receptor activation, but facilitates I-LTD induction via direct inhibition of cAMP-dependent protein kinase A (PKA) signaling. We further demonstrate that cAMP/PKA signaling pathway is the downstream effector for CB1 receptors and is required for eCB-mediated I-LTD induction. Our results suggest that D2 receptors and CB1 receptors target the same downstream effector cAMP/PKA signaling pathway to induce I-LTD and D2 receptor activation facilitates eCB-mediated I-LTD in dopamine neurons not by enhancing CB 1 receptor activation, but by enhancing its downstream effects.

Original languageEnglish (US)
Pages (from-to)14018-14030
Number of pages13
JournalJournal of Neuroscience
Volume28
Issue number52
DOIs
StatePublished - Dec 24 2008
Externally publishedYes

Keywords

  • cAMP/PKA
  • Dopamine
  • Endocannabinoid
  • GABA
  • Long-term depression
  • Synaptic plasticity

ASJC Scopus subject areas

  • General Neuroscience

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