Article

D-2 Dopamine Receptor Activation Facilitates Endocannabinoid-Mediated Long-Term Synaptic Depression of GABAergic Synaptic Transmission in Midbrain Dopamine Neurons via cAMP-Protein Kinase A Signaling

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 01/2009; 28(52):14018-30. DOI: 10.1523/JNEUROSCI.4035-08.2008
Source: PubMed

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, D(2) 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 D(2) 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 (CB(1)) receptors by the eCBs. By determining the downstream effectors for D(2) 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, D(2) receptor activation does not enhance CB(1) 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 CB(1) receptors and is required for eCB-mediated I-LTD induction. Our results suggest that D(2) receptors and CB(1) receptors target the same downstream effector cAMP/PKA signaling pathway to induce I-LTD and D(2) receptor activation facilitates eCB-mediated I-LTD in dopamine neurons not by enhancing CB(1) receptor activation, but by enhancing its downstream effects.

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