Faculty Collaboration Database

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. J Neurosci 2008 Dec 24;28(52):14018-30

Date

12/26/2008

Pubmed ID

19109485

Pubmed Central ID

PMC2656602

DOI

10.1523/JNEUROSCI.4035-08.2008

Scopus ID

2-s2.0-58149373942 (requires institutional sign-in at Scopus site)   110 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, 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.

Author List

Pan B, Hillard CJ, Liu QS

Authors

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Animals
Animals, Newborn
Benzoxazines
Chromones
Cocaine
Cyclic AMP-Dependent Protein Kinases
Dopamine
Dopamine Agents
Dopamine D2 Receptor Antagonists
Drug Combinations
Egtazic Acid
Electric Stimulation
Enzyme Inhibitors
Excitatory Amino Acid Antagonists
Female
In Vitro Techniques
Long-Term Synaptic Depression
Male
Mesencephalon
Mice
Mice, Knockout
Morpholines
Naphthalenes
Neurons
Patch-Clamp Techniques
Piperidines
Pyrazoles
Pyridines
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
Receptors, Dopamine D2
gamma-Aminobutyric Acid