Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation

Eur J Neurosci. 2002 Mar;15(6):953-61. doi: 10.1046/j.1460-9568.2002.01929.x.


Endocannabinoids are retrograde messengers that are released from central neurons by depolarization-induced elevation of intracellular Ca2+ concentration [Ca2+]I or by activation of a group I metabotropic glutamate receptor (mGluR). We studied the interaction between these two pathways for endocannabinoid production in rat hippocampal neurons. We made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. Activation of group I mGluRs, mainly mGluR5, by the specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), suppressed inhibitory postsynaptic currents (IPSCs) in about half of the neuron pairs. A cannabinoid agonist, WIN55,212-2, suppressed IPSCs in all DHPG-sensitive pairs but not in most of DHPG-insensitive pairs. The effects of both DHPG and WIN55,212-2 were abolished by the cannabinoid antagonists, AM281 and SR141716A, indicating that activation of group I mGluR releases endocannabinoids and suppress inhibitory neurotransmitter release through activation of presynaptic cannabinoid receptors. Depolarization of the postsynaptic neurons caused a transient suppression of IPSCs, a phemomenon termed depolarization-induced suppression of inhibition (DSI) that was also abolished by cannabinoid antagonists. Importantly, DSI was enhanced significantly when group I mGluRs were activated simultaneously by DHPG. This enhancement was much more prominent than expected from the simple summation of depolarization-induced and group I mGluR-induced endocannabinoid release. DHPG caused no change in depolarization-induced Ca2+ transients, indicating that the enhanced DSI by DHPG was not due to the augmentation of Ca2+ influx. Enhancement of DSI by DHPG was also observed in hippocampal slices. These results suggest that two pathways work in a cooperative manner to release endocannabinoids via a common intracellular cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzoxazines
  • Calcium Channel Blockers / pharmacology
  • Cannabinoid Receptor Modulators
  • Cannabinoids / biosynthesis*
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Endocannabinoids
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Methoxyhydroxyphenylglycol / analogs & derivatives*
  • Methoxyhydroxyphenylglycol / pharmacology
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Rats
  • Receptors, Cannabinoid
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Drug / metabolism
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, Metabotropic Glutamate / metabolism*
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*


  • Benzoxazines
  • Calcium Channel Blockers
  • Cannabinoid Receptor Modulators
  • Cannabinoids
  • Endocannabinoids
  • Excitatory Amino Acid Agonists
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Receptors, Metabotropic Glutamate
  • Methoxyhydroxyphenylglycol
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • 3,4-dihydroxyphenylglycol