Agomelatine affects rat suprachiasmatic nucleus neurons via melatonin and serotonin receptors.
OBJECTIVE
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-HT2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation.


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.


RESULTS
SCN firing rates were dose-dependently suppressed by 19.2-80.9% following perfusion of 0.04-0.32mM agomelatine (p<0.001, IC50=0.14mM). Perfusion with melatonin (0.4-3.2mM) resulted in 16.6-62.5% dose-dependent reductions in firing rates (at least p<0.01, IC50=1.59mM) and of the duration of suppression. A selective melatonin receptor antagonist (S22153 at 0.32mM) and a 5-HT2c receptor agonist (Ro60-0175) reduced the suppressive effects of 0.16mM agomelatine by 35% and 50.2%, respectively. A 5-HT2C receptor antagonist (S32006; 0.03-0.12mM) significantly decreased SCN firing rates (19.6-91.8%; at least p<0.05, IC50=0.05mM). Co-perfusion of S32006 (0.06mM) with a 5-HT2C agonist (Ro60-0175; 0.003mM) reduced suppressions evoked by S32006 alone by ~72.1%.


CONCLUSIONS
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-HT2C receptors, which parallel its mechanisms of action as an antidepressant.
Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, PR China.
Jing
J
Yang
Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, PR China.
Hui Juan
HJ
Jin
Innovation Therapeutic Pole Neuropsychiatry, Institut de Recherches Internationales Servier, Suresnes, France.
Elisabeth
E
Mocaër
Innovation Therapeutic Pole Neuropsychiatry, Institut de Recherches Internationales Servier, Suresnes, France.
Laure
L
Seguin
Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, PR China. Electronic address: zhua@jlu.edu.cn.
Hua
H
Zhao
Departments of Psychiatry, Psychology & Neuroscience and Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 2E2, Canada.
Benjamin
B
Rusak
D000081:Acetamides / Q000494:pharmacology*; D000200:Action Potentials; D000818:Animals; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes
D000081:Acetamides; D044094:Receptors, Melatonin; D011985:Receptors, Serotonin; C084711:agomelatine; D009281:Naphthalenes
5-HT(2C) receptors; Agomelatine; Brain slice; Firing rate; Melatonin; Neurophysiology; Suprachiasmatic nucleus