Abstract
Endocannabinoids serve as retrograde messengers in many brain regions. These diffusible lipophilic molecules are released by postsynaptic cells and regulate presynaptic neurotransmitter release. Here we describe an additional mechanism that mediates the spread of endocannabinoid signaling to distant inhibitory synapses. Depolarization of cerebellar Purkinje cells reduced the firing rate of nearby interneurons, and this reduction in firing was blocked by the cannabinoid receptor antagonist AM251. The cannabinoid receptor agonist WIN55,212-2 also reduced firing rates in interneurons, and this inhibition arose from the activation of a small potassium conductance. Thus, endocannabinoids released from the dendrites of depolarized neurons can lead to inhibition of firing in nearby cells. Because interneurons can project over several hundred micrometers, this inhibition of firing allows cells to regulate synaptic inputs at distances well beyond the limits of endocannabinoid diffusion.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Action Potentials / drug effects
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Action Potentials / physiology
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Animals
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Benzoxazines
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Calcium Channel Blockers / pharmacology
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Cannabinoid Receptor Modulators
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Cannabinoids / metabolism*
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Cerebellar Cortex / cytology
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Cerebellar Cortex / drug effects
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Cerebellar Cortex / metabolism*
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Dendrites / drug effects
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Dendrites / metabolism*
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Dendrites / ultrastructure
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Electric Stimulation
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Endocannabinoids
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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GABA Antagonists / pharmacology
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Interneurons / drug effects
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Interneurons / metabolism*
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Interneurons / ultrastructure
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Morpholines / pharmacology
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Naphthalenes / pharmacology
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Neural Inhibition / drug effects
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Neural Inhibition / physiology*
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Organ Culture Techniques
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Piperidines / pharmacology
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Potassium Channel Blockers / pharmacology
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Purkinje Cells / cytology
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Purkinje Cells / drug effects
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Purkinje Cells / metabolism*
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Pyrazoles / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Cannabinoid
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Receptors, Drug / agonists
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Receptors, Drug / antagonists & inhibitors
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Receptors, Drug / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Synapses / drug effects
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Synapses / metabolism
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Synapses / ultrastructure
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
Substances
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Benzoxazines
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Calcium Channel Blockers
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Cannabinoid Receptor Modulators
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Cannabinoids
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Endocannabinoids
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Excitatory Amino Acid Antagonists
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GABA Antagonists
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Morpholines
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Naphthalenes
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Piperidines
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Potassium Channel Blockers
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Pyrazoles
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Receptors, Cannabinoid
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Receptors, Drug
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AM 251
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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