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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 28, 2004; DOI: 10.1124/jpet.104.071860

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Received for publication May 25, 2004.
Revised May 25, 2004.
Accepted for publication May 28, 2004.

ETHANOL SUPPRESSION OF VENTRAL TEGMENTAL AREA GABA NEURON EPHAPTIC TRANSMISSION INVOLVES NMDA RECEPTORS

Sarah H. Stobbs 1, Allison J. Ohran 1, Matthew B. Lassen 1, David W. Allison 1, J. Elliott Brown 1, Scott C. Steffensen 1*

1 Brigham Young University

* Address correspondence to: E-mail: scott_steffensen{at}byu.edu

Abstract

Ventral tegmental area (VTA) GABA neurons are critical substrates modulating the mesocorticolimbic dopamine system implicated in natural and drug reward. The aim of this study was to evaluate the effects of ethanol on glutamatergic and GABAergic modulation of VTA GABA neuron electrical (ephaptic) synaptic transmission. We evaluated the effects of systemic ethanol (0.05-2.0 g/kg ip), the NMDA receptor antagonist dizocilpine (MK-801; 0.05-0.2 mg/kg iv), the connexin-36 gap junction blocker quinidine (5-20 mg/kg iv), the fast-acting barbiturate methohexital (Brevital; 5-10 mg/kg iv), and the benzodiazepine chlordiazepoxide (Librium; 5-10 mg/kg iv), as well as in situ VTA administration of NMDA and the GABAA receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule-evoked post-stimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, while local NMDA enhanced, and the systemic and local GABAA receptor modulators did not significantly alter VTA GABA neuron ICPSDs. Ethanol potentiated dizocilpine inhibition of VTA GABA neuron ICPSDs, but not quinidine inhibition. In situ microelectrophoretic application of dopamine markedly enhanced VTA GABA neuron firing rate (131%), spike duration (124%) and spike coupling, which were blocked by systemic quinidine. These findings indicate that VTA GABA neurons are coupled electrically via gap junctions, and that the inhibitory effect of ethanol on ephaptic transmission is primarily via inhibition of NMDA receptor-mediated excitation, not via enhancement of GABA receptor-mediated inhibition. Thus, the rewarding properties of ethanol may result from inhibitory effects on excitatory glutamatergic neurotransmission between electrically-coupled networks of midbrain GABA neurons.


Key words: Electrical Synapses, Ethanol, GABA, Gap Junctions, NMDA, Ventral Tegmental Area


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