Seizure susceptibility alteration through 5-HT(3) receptor: modulation by nitric oxide.
There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.
Gholipour
Taha
T
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Ghasemi
Mehdi
M
Riazi
Kiarash
K
Ghaffarpour
Majid
M
Dehpour
Ahmad Reza
AR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000139:chemically induced / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017829:Granisetron / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010433:Pentylenetetrazole; D010880:Piperidines / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology
D000927:Anticonvulsants; D001120:Arginine; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D017829:Granisetron; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D010433:Pentylenetetrazole; D010880:Piperidines; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C083009:4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride