title: Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling.
abstract: The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase α. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephanie.gantz@nih.gov.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Gantz
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bruce_bean@hms.harvard.edu.
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Bean
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005989:Glycerides / Q000494:pharmacology / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008636:Mesencephalon / Q000502:physiology*; D051379:Mice; D064446:Orexin Receptors / Q000819:agonists; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D018028:Receptors, Neurotensin / Q000819:agonists
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D064446:Orexin Receptors; D018094:Receptors, Metabotropic Glutamate; D018028:Receptors, Neurotensin; D016718:Arachidonic Acid; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase