The role of 5-HT3 receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of major depressive disorders. In addition to its antidepressant features, citalopram shows some anticonvulsive properties at lower doses, whereas higher doses, ingested in cases of suicide, have been associated with seizures. Moreover, some reports support the enhancing effect of morphine on different responses of SSRIs such as analgesic and anticonvulsant properties. Although the exact mechanisms of these additive effects are not yet fully understood, 5-HT3 receptor has recently been shown to play an important role in the central effects of SSRIs and morphine. In this regard, we used a model of clonic seizures induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether morphine and citalopram exhibit additive anticonvulsant effects and, if so, whether this effect is mediated through modulation of 5-HT3 receptors. In our study, citalopram at lower doses (0.5 and 1 mg/kg, ip) significantly increased the seizure threshold (P < 0.01) and at a higher dose (50 mg/kg) had proconvulsive effects. Moreover, morphine at low and noneffective doses had additive effects on the anticonvulsive properties of citalopram. This additive effect was prevented by pretreatment with low and noneffective doses of tropisetron (a 5-HT3 receptor antagonist) and augmented by 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT3 receptor agonist). Moreover, low doses of morphine (0.1 and 0.5 mg/kg) alone or in combination with potent doses of 5-HT3 receptor agonist or antagonist could not alter the proconvulsive properties of citalopram at higher dose (50 mg/kg), ruling out the contribution of 5-HT3 to this effect. In summary, our findings demonstrate that 5-HT3 receptor mediates the additive anticonvulsant properties of morphine and low-dose citalopram. This could constitute a new approach to augmenting the efficacy and curtailing the adverse effects of citalopram. (C) 2011 Elsevier Inc. All rights reserved.