Ondansetron modulates GABA(A) current of rat central nervous system neurons.
We examined the effect of ondansetron, a 5-HT3 receptor antagonist, on the whole cell current response of freshly isolated hypothalamic and hippocampal neurons of rats to gamma-aminobutyric acid (GABA). The nystatin perforated patch technique was used to minimize run-down of the GABA current. While 1-150 microM ondansetron had no effect on membrane conductance, co-application with agonist reversibly depressed the maximal end GABA current. The concentration-response relation of GABA reveals a non-competitive mechanism. However, the inhibitory effect was more potent when ondansetron was co-applied with lower concentrations of GABA: i.e., the ondansetron concentration needed to depress the current induced by 5 microM GABA to half amplitude was 7 microM compared to 28 microM for the current induced by 10 microM GABA. Analysis of the current-voltage relationship with and without ondansetron indicated that the effect of ondansetron is not voltage dependent. Current-voltage relations also showed that the effect of ondansetron was not due to activation of a GABA-independent current because the reversal potentials were the same with and without ondansetron. The present data suggest that ondansetron's suppression of GABA-activated current may be the molecular basis of ondansetron-induced seizures observed in vivo.
Ye
J H
JH
Department of Anesthesiology, New Jersey Medical School (UMDNJ), Newark 07103-2714, USA. ye@umdnj.edu
Hunt
T
T
Wu
W H
WH
McArdle
J J
JJ
D000818:Animals; D004594:Electrophysiology; D018757:GABA Modulators / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017294:Ondansetron / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000633:toxicity*
D018757:GABA Modulators; D011963:Receptors, GABA-A; D012702:Serotonin Antagonists; D017294:Ondansetron