Involvement of serotonin in the modulation of cocaine-induced locomotor activity in the rat.

The influence of serotonin (5-HT) antagonists and a selective serotonin reuptake inhibitor (SSRI) on cocaine-induced locomotor activity, rears, and head bobs was investigated in female Glaxo Wistar rats. The SSRI, fluoxetine (10 mg/kg), and the nonselective 5-HT agent, methysergide, at the dose range of 5 and 15 mg/kg enhanced the behaviors produced by cocaine (15 mg/kg) to a similar extent. Moreover, the potentiation of cocaine-induced locomotor activity, rears, and head bobs was even greater after the combined administration of methysergide ( 15 mg/kg) and fluoxetine (10 mg/kg). In order to investigate a possible involvement of 5-HT1A receptors in the observed potentiation by methysergide and fluoxetine, the potent and selective 5-HT1A antagonist, WAY 100635, was used. WAY 100635 (0.1 and 1.5 mg/kg) markedly reduced the behaviors induced by cocaine preceded by fluoxetine (10 mg/kg) and methysergide (5 and 15 mg/kg) pretreatment, respectively, suggesting an involvement of 5-HT1A receptors in the action of fluoxetine and methysergide on cocaine-induced behaviors. An attenuation of the fluoxetine-enhanced cocaine-induced behaviors was also observed after pretreatment with the 5-HT2A antagonist ketanserin (0.1 and 1.0 mg/kg). Coadministration of ketanserin (1.0 mg/kg) and WAY 100635 (1.5 mg/kg) resulted in the greatest blockade of the fluoxetine-enhanced cocaine-induced behaviors. The antagonists and the SSRI, fluoxetine, did not alter the behaviors in comparison to that of saline-treated animals. These results provide evidence for an involvement of 5-HT1A receptors in the enhancing effect of fluoxetine and methysergide on cocaine-induced locomotor activity, rears, and head bobs, and suggest a stimulatory action of methysergide at the 5-HT1A receptor. In addition, some of the actions may also be mediated by activation of the 5-HT2A receptor and/or inhibition of the 5-HT2C receptor.