Role of 5-hydroxytryptamine2C receptors in Ca2+-dependent ethanol potentiation of GABA release onto ventral tegmental area dopamine neurons.
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 Ca(2+) levels regulate neurotransmitter release, we investigated the roles of Ca(2+)-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 Ca(2+) 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 Ca(2+) 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 [(alphaS)-6-chloro-5-fluoro-alpha-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 Ca(2+) release from intracellular stores via 5-HT(2C) receptor activation is involved in the ethanol-induced enhancement of GABA release onto VTA-DA neurons.
Theile
Jonathan W
JW
Cell and Molecular Biology, College of Pharmacy, University of Texas, Austin, TX 78712-0125, USA. jontheile@mail.utexas.edu
Morikawa
Hitoshi
H
Gonzales
Rueben A
RA
Morrisett
Richard A
RA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005021:Ethylamines / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005021:Ethylamines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; C080864:N-(1-methyl-5-indolyl)-N'-(3-pyridyl)urea; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D014508:Urea; D002118:Calcium; D004298:Dopamine