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.