Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area

Ferenc Mátyás, Gabriella M. Urbán, Masahiko Watanabe, Ken Mackie, Andreas Zimmer, T. Freund, I. Katona

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

Intact endogenous cannabinoid signaling is involved in several aspects of drug addiction. Most importantly, endocannabinoids exert pronounced influence on primary rewarding effects of abused drugs, including exogenous cannabis itself, through the regulation of drug-induced increase in bursting activity of dopaminergic neurons in the ventral tegmental area (VTA). Previous electrophysiological studies have proposed that these dopaminergic neurons may release endocannabinoids in an activity-dependent manner to regulate their various synaptic inputs; however, the underlying molecular and anatomical substrates have so far been elusive. To facilitate understanding of the neurobiological mechanisms involving endocannabinoid signaling in drug addiction, we carried out detailed analysis of the molecular architecture of the endocannabinoid system in the VTA. In situ hybridization for sn-1-diacylglycerol lipase-alpha (DGL-α), the biosynthetic enzyme of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), revealed that DGL-α was expressed at moderate to high levels by most neurons of the VTA. Immunostaining for DGL-α resulted in a widespread punctate pattern at the light microscopic level, whereas high-resolution electron microscopic analysis demonstrated that this pattern is due to accumulation of the enzyme adjacent to postsynaptic specializations of several distinct morphological types of glutamatergic and GABAergic synapses. These axon terminal types carried presynaptic CB1 cannabinoid receptors on the opposite side of DGL-α-containing synapses and double immunostaining confirmed that DGL-α is present on the plasma membrane of both tyrosine hydroxylase (TH)-positive (dopaminergic) and TH-negative dendrites. These findings indicate that retrograde synaptic signaling mediated by 2-AG via CB1 may influence the drug-reward circuitry at multiple types of synapses in the VTA.

Original languageEnglish
Pages (from-to)95-107
Number of pages13
JournalNeuropharmacology
Volume54
Issue number1
DOIs
Publication statusPublished - Jan 2008

Fingerprint

Endocannabinoids
Ventral Tegmental Area
Lipoprotein Lipase
Synapses
Dopaminergic Neurons
Tyrosine 3-Monooxygenase
Substance-Related Disorders
Cannabinoid Receptor CB1
Cannabinoids
Drug and Narcotic Control
Presynaptic Terminals
Enzymes
Cannabis
Dendrites
Reward
Pharmaceutical Preparations
In Situ Hybridization
Cell Membrane
2-arachidonylglycerol
Electrons

Keywords

  • Addiction
  • Cannabinoid
  • CB
  • DAGL
  • DGL-α
  • Dopamine
  • Synaptic plasticity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. / Mátyás, Ferenc; Urbán, Gabriella M.; Watanabe, Masahiko; Mackie, Ken; Zimmer, Andreas; Freund, T.; Katona, I.

In: Neuropharmacology, Vol. 54, No. 1, 01.2008, p. 95-107.

Research output: Contribution to journalArticle

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