Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

Stephanie C Gantz; Bruce P Bean

doi:10.1016/j.neuron.2017.02.025

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Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

Journal article

Open access

Peer reviewed

Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

Stephanie C Gantz and Bruce P Bean

Neuron (Cambridge, Mass.), Vol.93(6), pp.1375-1387.e2

03/22/2017

DOI: 10.1016/j.neuron.2017.02.025

PMCID: PMC5672336

PMID: 28262417

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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 (I ) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate G -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 I .

Arachidonic Acids - physiology

Membrane Potentials - drug effects

Lipoprotein Lipase - antagonists & inhibitors

Endocannabinoids - pharmacology

Male

Membrane Potentials - physiology

Arachidonic Acids - pharmacology

Action Potentials - physiology

Receptors, Neurotensin - agonists

Endocannabinoids - physiology

Glycerides - pharmacology

Animals

Glycerides - physiology

Arachidonic Acid - pharmacology

Dopaminergic Neurons - drug effects

Dopaminergic Neurons - physiology

Orexin Receptors - agonists

Female

Mice

Mesencephalon - physiology

Receptors, Metabotropic Glutamate - agonists

Action Potentials - drug effects

Details

Title: Subtitle: Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling
Creators: Stephanie C Gantz - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephanie.gantz@nih.gov
Bruce P Bean - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bruce_bean@hms.harvard.edu
Resource Type: Journal article
Publication Details: Neuron (Cambridge, Mass.), Vol.93(6), pp.1375-1387.e2
Publisher: United States
DOI: 10.1016/j.neuron.2017.02.025
PMID: 28262417
PMCID: PMC5672336
ISSN: 0896-6273
eISSN: 1097-4199
Grant note: R01 NS036855 / NINDS NIH HHS
Language: English
Date published: 03/22/2017
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984065370902771

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