1. ¹Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA
2. ²Department of Physiology and Pharmacology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA
3. ³Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
4. ⁴Department of Psychiatry and Behavioral Sciences, Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC, USA
5. ⁵Department of Physiology , McGill University, Montréal, QC, Canada

Correspondence: Dr J-H Ye, Department of Anesthesiology, UMDNJ, New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103, USA. Tel: +1 973 972 1866; Fax: +1 973 972 4172; E-mail: ye@umdnj.edu

Received 12 November 2007; Revised 31 March 2008; Accepted 19 May 2008; Published online 2 July 2008.

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 -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.