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The Journal of Neuroscience, December 24, 2008, 28(52):14018-14030; doi:10.1523/JNEUROSCI.4035-08.2008

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Behavioral/Systems/Cognitive
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, and Qing-song Liu

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Correspondence should be addressed to Qing-song Liu at the above address. Email: qsliu{at}mcw.edu

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 CB₁ 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 CB₁ receptor activation, but by enhancing its downstream effects.

Key words: endocannabinoid; long-term depression; synaptic plasticity; GABA; cAMP/PKA; dopamine

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Received Aug. 24, 2008; revised Oct. 6, 2008; accepted Oct. 28, 2008.

Correspondence should be addressed to Qing-song Liu at the above address. Email: qsliu{at}mcw.edu

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