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 synaptic transmission. We evaluated the effects of systemic ethanol (0.05–2.0 g/kg i.p.), the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801; 0.05–0.2 mg/kg i.v.), the connexin-36 gap junction blocker quinidine (5–20 mg/kg i.v.), the fast-acting barbiturate methohexital (Brevital; 5–10 mg/kg i.v.), and the benzodiazepine chlordiazepoxide (Librium; 5–10 mg/kg i.v.), as well as in situ VTA administration of NMDA and the GABAA receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule stimulus-induced poststimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, whereas 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 electrical 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.
Footnotes
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This work was funded by Public Health Service Grant AA13666 to S.C.S.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.071860.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; VTA, ventral tegmental area; PSD, poststimulus spike discharge; ICPSD, internal capsule stimulus-induced poststimulus spike discharge; PSH, peristimulus spike histogram.
- Received May 25, 2004.
- Accepted May 28, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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