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

• Published in: The Journal of neuroscience 2008-12, Vol.28 (52), p.14018-14030
• Main Authors: Pan, Bin, Hillard, Cecilia J, Liu, Qing-song
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Benzoxazines - pharmacology; Chromones - pharmacology; Cocaine - pharmacology; Cyclic AMP-Dependent Protein Kinases - physiology; Dopamine - metabolism; Dopamine Agents - pharmacology; Dopamine D2 Receptor Antagonists; Drug Combinations; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Electric Stimulation - methods; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Female; gamma-Aminobutyric Acid - metabolism; In Vitro Techniques; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Male; Mesencephalon - cytology; Mice; Mice, Knockout; Morpholines - pharmacology; Naphthalenes - pharmacology; Neurons - drug effects; Neurons - physiology; Patch-Clamp Techniques - methods; Piperidines - pharmacology; Pyrazoles - pharmacology; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - deficiency; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.4035-08.2008

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.