Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area

Cheng Xiao, Xuesi Max Shao, M. Foster Olive, William C. Griffin, Ke Yong Li, Kresimir Krnjević, Chunyi Zhou, Jiang Hong Ye

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

The cellular mechanisms underlying alcohol addiction are poorly understood. In several brain areas, ethanol depresses glutamatergic excitatory transmission, but how it affects excitatory synapses on dopamine neurons of the ventral tegmental area (VTA), a crucial site for the development of drug addiction, is not known. We report here that in midbrain slices from rats, clinically relevant concentrations of ethanol (10-80 mM) increase the amplitude of evoked EPSCs and reduce their paired-pulse ratio in dopamine neurons in the VTA. The EPSCs were mediated by glutamate α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) receptors. In addition, ethanol increases the frequency but not the amplitude of spontaneous EPSCs. Furthermore, ethanol increases extracellular glutamate levels in the VTA of midbrain slices. The effects of ethanol are mimicked by SKF 38393, a dopamine D1 receptor agonist, and by GBR 12935, a dopamine reuptake inhibitor, and they are blocked by SKF 83566, a D1 antagonist, or by reserpine, which depletes dopamine stores. The enhancement of sEPSC frequency reaches a peak with 40 mM ethanol and declines with concentrations ≥80 mM ethanol, which is quite likely a result of D2 receptor activation as raclopride, a D2 receptor blocker, significantly enhanced 80 mM ethanol-induced enhancement of sEPSCs. Finally, 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), an AMPA receptor antagonist, attenuates ethanol-induced excitation of VTA DA neurons. We therefore conclude that, acting via presynaptic D1 receptors, ethanol at low concentrations increases glutamate release in the VTA, thus raising somatodendritic dopamine release, which further activates the presynaptic D1 receptors. Enhancement of this positive feedback loop may significantly contribute to the development of alcohol addiction.

Original languageEnglish (US)
Pages (from-to)307-318
Number of pages12
JournalNeuropsychopharmacology
Volume34
Issue number2
DOIs
StatePublished - Jan 2009

Keywords

  • Addiction
  • Alcohol
  • D and D receptors
  • Glutamate
  • Mesolimbic system
  • Raclopride

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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