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NEUROPHARMACOLOGY

Role of 5-Hydroxytryptamine_2C Receptors in Ca²⁺-Dependent Ethanol Potentiation of GABA Release onto Ventral Tegmental Area Dopamine Neurons

Cell and Molecular Biology (J.W.T., H.M., R.A.M.), Waggoner Center for Alcohol and Addiction Research (H.M., R.A.G., R.A.M.), Section of Neurobiology (H.M.), and Division of Pharmacology and Toxicology (R.A.G., R.A.M.), College of Pharmacy, University of Texas, Austin, Texas

Activation of ventral tegmental area (VTA)-dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. We have reported previously that ethanol enhances GABA release onto VTA-DA neurons in a brain slice preparation. Because intraterminal Ca²⁺ levels regulate neurotransmitter release, we investigated the roles of Ca²⁺-dependent mechanisms in ethanol-induced enhancement of GABA release. Acute ethanol enhanced miniature inhibitory postsynaptic current (mIPSC) frequency in the presence of the nonspecific voltage-gated Ca²⁺ channel inhibitor, cadmium chloride, even though basal mIPSC frequency was reduced by cadmium. Conversely, the inositol-1,4,5-triphosphate receptor inhibitor, 2-aminoethoxydiphenylborane, and the sarco/endoplasmic reticulum Ca²⁺ ATPase pump inhibitor, cyclopiazonic acid, eliminated the ethanol enhancement of mIPSC frequency. Recent studies suggest that the G protein-coupled receptor, 5-hydroxytryptamine (5-HT) _2C, may modulate GABA release in the VTA. Thus, we also investigated the role of 5-HT_2C receptors in ethanol enhancement of GABAergic transmission. Application of 5-HT and the 5-HT_2C receptor agonist, Ro-60-0175 [(S)-6-chloro-5-fluoro--methyl-1H-indole-1-ethanamine fumarate], alone enhanced mIPSC frequency of which the latter was abolished by the 5-HT_2C receptor antagonist, SB200646 [N-(1-methyl-5-indoyl)-N-(3-pyridyl)urea hydrochloride], and substantially diminished by cyclopiazonic acid. Furthermore, SB200646 abolished the ethanol-induced increase in mIPSC frequency and had no effect on basal mIPSC frequency. These observations suggest that an increase in Ca²⁺ release from intracellular stores via 5-HT_2C receptor activation is involved in the ethanol-induced enhancement of GABA release onto VTA-DA neurons.

Address correspondence to: Jonathan Theile, University of Texas, PHAR-Pharmacology, 1 University Station, A1915, Austin, TX 78712-0125. E-mail: jontheile{at}mail.utexas.edu