RT Journal Article
SR Electronic
T1 Role of 5-Hydroxytryptamine<sub>2C</sub> Receptors in Ca<sup>2+</sup>-Dependent Ethanol Potentiation of GABA Release onto Ventral Tegmental Area Dopamine Neurons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 625
OP 633
DO 10.1124/jpet.108.147793
VO 329
IS 2
A1 Jonathan W. Theile
A1 Hitoshi Morikawa
A1 Rueben A. Gonzales
A1 Richard A. Morrisett
YR 2009
UL http://jpet.aspetjournals.org/content/329/2/625.abstract
AB 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-HT2C receptors in ethanol enhancement of GABAergic transmission. Application of 5-HT and the 5-HT2C receptor agonist, Ro-60-0175 [(αS)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate], alone enhanced mIPSC frequency of which the latter was abolished by the 5-HT2C 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-HT2C receptor activation is involved in the ethanol-induced enhancement of GABA release onto VTA-DA neurons. The American Society for Pharmacology and Experimental Therapeutics