Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus

Jimok Kim, Masako Isokawa, Catherine Ledent, Bradley E. Alger

Research output: Contribution to journalArticle

233 Citations (Scopus)

Abstract

Endogenous cannabinoids (endocannabinoids) are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to both inhibitory ["depolarization-induced suppression of inhibition" (DSI)] and excitatory ("depolarization-induced suppression of excitation") afferent fibers. Transient endocannabinoid release is triggered by voltage-dependent Ca2+ influx and is upregulated by group I metabotropic glutamate receptor activation. Here we show that muscarinic acetylcholine receptor (mAChR) activation also enhances transient endocannabinoid release (DSI) and induces persistent release. Inhibitory synapses in the rat hippocampal CA1 region of acute slices were studied using whole-cell patch-clamp techniques. We found that low concentrations (0.2-0.5 μM) of carbachol (CCh) enhanced DSI without affecting basal evoked IPSCs (elPSCs) by activating mAChRs on postsynaptic cells. Higher concentrations of CCh (≥1 μM) enhanced DSI and also persistently depressed basal eIPSCs, mainly by releasing endocannabinoids. Persistent CCh-induced endocannabinoid release did not require an increase in [Ca2+]i but was dependent on G-proteins. Although they were independent at the receptor level, muscarinic and glutamatergic mechanisms of endocannabinoid release shared intracellular machinery. Replication of the effects of CCh by blocking acetylcholinesterase with eserine suggests that mAChR-mediated endocannabinoid release is physiologically relevant. This study reveals a new role of the muscarinic cholinergic system in mammalian brain.

Original languageEnglish (US)
Pages (from-to)10182-10191
Number of pages10
JournalJournal of Neuroscience
Volume22
Issue number23
StatePublished - Dec 1 2002

Fingerprint

Cannabinoids
Muscarinic Receptors
Hippocampus
Carbachol
Cholinergic Agents
Hippocampal CA1 Region
Cannabinoid Receptors
Physostigmine
Metabotropic Glutamate Receptors
Brain
Patch-Clamp Techniques
Cannabis
Acetylcholinesterase
GTP-Binding Proteins
Synapses

Keywords

  • DSI
  • GABAergic IPSC
  • MAChR
  • MGluR
  • Retrograde messenger
  • Retrograde signaling

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. / Kim, Jimok; Isokawa, Masako; Ledent, Catherine; Alger, Bradley E.

In: Journal of Neuroscience, Vol. 22, No. 23, 01.12.2002, p. 10182-10191.

Research output: Contribution to journalArticle

Kim, Jimok ; Isokawa, Masako ; Ledent, Catherine ; Alger, Bradley E. / Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 23. pp. 10182-10191.
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