Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep-wake cycle architecture.
BACKGROUND
The novel antidepressant, agomelatine, behaves as an agonist at melatonin MT(1) and MT(2) receptors and as an antagonist at serotonin (5-HT)(2C) receptors. In animal models and clinical trials, agomelatine displays antidepressant properties and re-synchronizes disrupted circadian rhythms.


OBJECTIVE
The objectives of this study were to compare the influence of agomelatine upon sleep-wake states to the selective melatonin agonists, melatonin and ramelteon, and to the selective 5-HT(2C) receptor antagonist, S32006.


METHODS
Rats were administered with vehicle, agomelatine, ramelteon, melatonin, or S32006, at the onset of either dark or light periods. Polygraphic recordings were performed and changes determined over 24 h, i.e., number and duration of sleep-wake episodes, latencies to rapid eye movement (REM) and slow-wave (SWS) sleep, power band spectra of the electroencephalogram (EEG), and circadian changes.


RESULTS
Administered at light phase onset, no changes were induced by agomelatine. In contrast, administered shortly before dark phase, agomelatine (10 and 40 mg/kg, per os) enhanced duration of REM and SWS sleep and decreased wake state for 3 h. Melatonin (10 mg/kg, per os) induced a transient enhancement in REM sleep followed by a reduction in REM and SWS sleep and an increase in waking. Ramelteon (10 mg/kg, per os) provoked a transient increase in REM sleep. Finally, S32006 (10 mg/kg, intraperitoneally), administered at dark phase onset, mimicked the increased SWS provoked by agomelatine, yet diminished REM sleep.


CONCLUSIONS
Agomelatine possesses a distinctive EEG profile compared with melatonin, ramelteon, and S32006, possibly reflecting co-joint agonist and antagonist properties at MT(1)/MT(2) and 5-HT(2C) receptors, respectively.
Claude Bernard University, Lyon, EA4170, France. amandine.lefebvre@sante.univ-lyon1.fr
Amandine
A
Descamps
Colette
C
Rousset
Mark J
MJ
Millan
Mark
M
Millan
Michael
M
Spedding
Philippe
P
Delagrange
Raymond
R
Cespuglio
D000081:Acetamides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002940:Circadian Rhythm / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008550:Melatonin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*; D009281:Naphthalenes
D000081:Acetamides; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D007192:Indenes; D007211:Indoles; D008550:Melatonin; D011725:Pyridines; D012702:Serotonin Antagonists; C533966:S32006; C084711:agomelatine; D009281:Naphthalenes; C495910:ramelteon