Agomelatine affects rat suprachiasmatic nucleus neurons via melatonin and serotonin receptors

Aims The hypothalamic suprachiasmatic nucleus (SCN), which functions as a circadian pacemaker in mammals, is influenced by melatonin and serotonin. Agomelatine, which acts as an antidepressant and can synchronize disturbed circadian rhythms, displays a unique mechanism of action involving both melatonergic agonist and 5-HT_2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT_2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation. Main methods Brain slices containing the SCN were prepared from male Wistar rats and maintained in a recording chamber. Changes in firing rates of SCN neurons were recorded after perfusion of drugs. Key findings SCN firing rates were dose-dependently suppressed by 19.2-80.9% following perfusion of 0.04-0.32 mM agomelatine (p < 0.001, IC₅₀ = 0.14 mM). Perfusion with melatonin (0.4-3.2 mM) resulted in 16.6-62.5% dose-dependent reductions in firing rates (at least p < 0.01, IC₅₀ = 1.59 mM) and of the duration of suppression. A selective melatonin receptor antagonist (S22153 at 0.32 mM) and a 5-HT_2c receptor agonist (Ro60-0175) reduced the suppressive effects of 0.16 mM agomelatine by 35% and 50.2%, respectively. A 5-HT_2C receptor antagonist (S32006; 0.03-0.12 mM) significantly decreased SCN firing rates (19.6-91.8%; at least p < 0.05, IC₅₀ = 0.05 mM). Co-perfusion of S32006 (0.06 mM) with a 5-HT_2C agonist (Ro60-0175; 0.003 mM) reduced suppressions evoked by S32006 alone by ~ 72.1%. Significance These results are consistent with the hypothesis that agomelatine acts directly on the SCN via both agonist effects at melatonergic receptors and antagonist effects at 5-HT_2C receptors, which parallel its mechanisms of action as an antidepressant.