Seizure susceptibility alteration through 5-HT(3) receptor: modulation by nitric oxide

Seizure. 2010 Jan;19(1):17-22. doi: 10.1016/j.seizure.2009.10.006. Epub 2009 Nov 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology
  • Arginine / pharmacology
  • Disease Models, Animal
  • Disease Susceptibility / chemically induced
  • Disease Susceptibility / physiopathology*
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Interactions / physiology
  • Enzyme Inhibitors / pharmacology
  • Granisetron / pharmacology
  • Male
  • Mice
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism*
  • Pentylenetetrazole
  • Piperidines / pharmacology
  • Receptors, Serotonin, 5-HT3 / physiology*
  • Seizures / chemically induced
  • Seizures / drug therapy
  • Seizures / metabolism*
  • Serotonin Antagonists / pharmacology


  • Anticonvulsants
  • Drug Combinations
  • Enzyme Inhibitors
  • Piperidines
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Nitric Oxide
  • Arginine
  • 4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride
  • NG-Nitroarginine Methyl Ester
  • Pentylenetetrazole
  • Granisetron