title: Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum.
abstract: Endocannabinoids are important mediators of short- and long-term synaptic plasticity, but the mechanisms of endocannabinoid release have not been studied extensively outside the hippocampus and cerebellum. Here, we examined the mechanisms of endocannabinoid-mediated long-term depression (eCB-LTD) in the dorsal striatum, a brain region critical for motor control and reinforcement learning. Unlike other cell types, strong depolarization of medium spiny neurons was not sufficient to yield detectable endocannabinoid release. However, when paired with postsynaptic depolarization sufficient to activate L-type calcium channels, activation of postsynaptic metabotropic glutamate receptors (mGluRs), either by high-frequency tetanic stimulation or an agonist, induced eCB-LTD. Pairing bursts of afferent stimulation with brief subthreshold membrane depolarizations that mimicked down-state to up-state transitions also induced eCB-LTD, which not only required activation of mGluRs and L-type calcium channels but also was bidirectionally modulated by dopamine D2 receptors. Consistent with network models, these results demonstrate that dopamine regulates the induction of a Hebbian form of long-term synaptic plasticity in the striatum. However, this gating of plasticity by dopamine is accomplished via an unexpected mechanism involving the regulation of mGluR-dependent endocannabinoid release.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Palo Alto, California 94305, USA.
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D004298:Dopamine / Q000494:pharmacology* / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D004843:Epistasis, Genetic; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009568:Nitrendipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013469:Sulpiride / Q000494:pharmacology; D013997:Time Factors
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; C120673:benzyloxyaspartate; D019257:Quinpirole; D001224:Aspartic Acid; C103505:AM 251; D008734:Methoxyhydroxyphenylglycol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013469:Sulpiride; D009568:Nitrendipine; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine