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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Benzoxazines / pharmacology
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Chromones / pharmacology
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Cocaine / pharmacology
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Cyclic AMP-Dependent Protein Kinases / physiology*
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Dopamine / metabolism*
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Dopamine Agents / pharmacology
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Dopamine D2 Receptor Antagonists
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Drug Combinations
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacology
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Electric Stimulation / methods
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Female
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In Vitro Techniques
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / physiology*
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Male
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Mesencephalon / cytology*
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Mice
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Mice, Knockout
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Morpholines / pharmacology
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Naphthalenes / pharmacology
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Neurons / drug effects
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Neurons / physiology*
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Patch-Clamp Techniques / methods
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Piperidines / pharmacology
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / deficiency
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D2 / physiology*
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gamma-Aminobutyric Acid / metabolism*
Substances
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7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester
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Benzoxazines
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Chromones
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Dopamine Agents
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Dopamine D2 Receptor Antagonists
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Drug Combinations
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Morpholines
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Naphthalenes
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Piperidines
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Pyrazoles
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Pyridines
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Receptor, Cannabinoid, CB1
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Receptors, Dopamine D2
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AM 251
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Egtazic Acid
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gamma-Aminobutyric Acid
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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6-methyl-2-(phenylethynyl)pyridine
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EGTA acetoxymethyl ester
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Cyclic AMP-Dependent Protein Kinases
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Cocaine
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Dopamine