Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: A comparison to melatonin and to the 5-HT2c antagonist, S32006

The novel melatonergic agonist/5-HT2C antagonist agomelatine displays robust antidepressant properties in humans and is active in pre-clinical models predictive of antidepressant effects. In this study, we investigated its potential influence on the locomotor hyperactivity displayed by olfactory bulbectomised rats, a putative measure of potential antidepressant activity. In addition, we compared the actions of agomelatine to those of melatonin and S32006, a selective antagonist at 5-HT2C receptors. Vehicle, agomelatine (10 and 50 mg/kg), melatonin (10 and 50 mg/kg), S32006 (0.16 mg/kg to 10 mg/kg) and the prototypical tricyclic antidepressant, imipramine (10 mg/kg), were administered by intraperitoneal injection for 14 days to male, Sprague-Dawley sham-operated and bulbectomised rats. In agreement with previous studies, imipramine was active in the model and both the lower and higher doses of agomelatine also significantly and markedly reversed the bulbectomy-induced hyperactivity to a level comparable to that seen in sham operated animals, in which agomelatine exerted no effect. Similarly the 5-HT2C antagonist, S32006, dose-dependently and significantly attenuated hyperactivity of bulbectomised animals, albeit with a maximal effect somewhat less marked than that of agomelatine. On the other hand, melatonin did not affect the locomotor behaviour of bulbectomised rats. The activity of agomelatine in the model is consistent with its known antidepressant properties in the clinic.