Ethanol Facilitates Glutamatergic Transmission to Dopamine Neurons in the Ventral Tegmental Area

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

doi:10.1038/npp.2008.99

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 alpha-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 D(1) receptor agonist, and by GBR 12935, a dopamine reuptake inhibitor, and they are blocked by SKF 83566, a D(1) antagonist, or by reserpine, which depletes dopamine stores. The enhancement of sEPSC frequency reaches a peak with 40 mM ethanol and declines with concentrations >or=80 mM ethanol, which is quite likely a result of D(2) receptor activation as raclopride, a D(2) 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 D(1) receptors, ethanol at low concentrations increases glutamate release in the VTA, thus raising somatodendritic dopamine release, which further activates the presynaptic D(1) receptors. Enhancement of this positive feedback loop may significantly contribute to the development of alcohol addiction.

Highlights

Numerous studies have associated the mesolimbic dopaminergic (DA) system, originating from the ventral tegmental area (VTA), with ethanol addiction
Bearing in mind that genetic deletion of D1 receptors (D1R) reduces ethanol consumption (El-Ghundi et al, 1998) and that firing by 0.2 mM quinpirole, a dopamine D2/D3 receptor agonist, and facilitation by 1 mM DAMGO, a m-opioid receptor agonist, are characteristic features of VTA DA neurons synapsing onto VTA DA neurons (Lu et al, 1997), we
To assess the contribution of glutamatergic transmission to the overall facilitating action of ethanol, we examined the effect of 10 mM DNQX on the ethanol-induced increase in spontaneous firing of putative DA neurons

Summary

INTRODUCTION

Numerous studies have associated the mesolimbic dopaminergic (DA) system, originating from the ventral tegmental area (VTA), with ethanol addiction. Bearing in mind that genetic deletion of D1Rs reduces ethanol consumption (El-Ghundi et al, 1998) and that firing by 0.2 mM quinpirole, a dopamine D2/D3 receptor agonist, and facilitation by 1 mM DAMGO, a m-opioid receptor agonist (as a result of DAMGO-induced disinhibiethanol stimulates somatodendritic dopamine release, tion of inhibitory GABAergic neurons in the VTA, which may activate D1Rs expressed on GLUergic axons Figure 1c), are characteristic features of VTA DA neurons synapsing onto VTA DA neurons (Lu et al, 1997), we To examine this possibility, we analyzed the effects of acute et al, 2003). Voltage sag in response to a hyperpolarizing current pulse (between À100 and 0 pA, Figure 1d, right panel)

MATERIALS AND METHODS

DISCUSSION

Findings

DISCLOSURE