5-HT(3) receptor mediates the dose-dependent effects of citalopram on pentylenetetrazole-induced clonic seizure in mice: involvement of nitric oxide

Epilepsy Res. 2012 Sep;101(3):217-27. doi: 10.1016/j.eplepsyres.2012.04.004. Epub 2012 May 9.


Citalopram is a selective serotonin reuptake inhibitor (SSRI), widely used in the treatment of depressive disorders. It has been shown that citalopram affects seizure susceptibility. Although the exact mechanism of these effects are not yet fully understood, recent data suggest that 5HT(3) receptors and nitric oxide (NO) might participate in the central effects of SSRIs. In this study in a mouse model of clonic seizure induced by pentylenetetrazole we investigated whether 5-HT(3) receptors are involved in the effects of citalopram on seizure threshold. In our experiments, citalopram at lower doses (0.5 and 1mg/kg, i.p) significantly increased the seizure threshold and at higher doses (≥25mg/kg) showed proconvulsive effects. Moreover, mCPBG (a 5-HT(3) receptor agonist) at low and non-effective doses augmented while non-effective doses of tropisetron prevented the anticonvulsive properties of citalopram. On the other hand, Low doses of nitric oxide synthase inhibitors l-NAME and 7-NI alone or in combination with lower doses of 5-HT(3) receptor agonist enhanced the anticonvulsive property of citalopram, while l-arginine (NO precursor) alone or in combination with tropisetron blocked the protective effect of citalopram. In summary, our findings demonstrate that 5-HT(3) receptor mediates the anticonvulsant properties of low doses of citalopram, whereas it seems that the proconvulsive effect is mostly mediated through the NO pathway and can be totally blocked by NOS inhibitors. This could propose a new approach toward finding the mechanism of citalopram activity, curtailing the adverse effects of citalopram and perhaps managing the convulsions as a vicious consequence of citalopram overdose.

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology
  • Anticonvulsants / therapeutic use*
  • Biguanides / pharmacology
  • Citalopram / pharmacology
  • Citalopram / therapeutic use*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Male
  • Mice
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Pentylenetetrazole / adverse effects
  • Receptors, Serotonin, 5-HT3 / metabolism*
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Seizures / metabolism
  • Serotonin Receptor Agonists / pharmacology


  • Anticonvulsants
  • Biguanides
  • Enzyme Inhibitors
  • Receptors, Serotonin, 5-HT3
  • Serotonin Receptor Agonists
  • Citalopram
  • Nitric Oxide
  • 1-(3-chlorophenyl)biguanide
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester
  • Pentylenetetrazole