Effects of agomelatine compared to melatonin in psychosocially stressed tree shrews, an animal model of depression

It is well known that depressive disorders are associated with desynchronization of internal rhythms stimulating the idea that resetting circadian rhythms may have antidepressant potential. Agomelatine is a new melatonergic (MT₁ and MT₂) receptor agonist and serotonergic 5-HT_2c receptor antagonist with notable chronobiotic activity in different animal models (van Reeth et al, 2001). Moreover, agomelatine showed antidepressant-like activity in several preclinical models of depression. In the present study we investigated the effect of agomelatine compared to melatonin on body weight, core body temperature (CBT), HPA activity and locomotor activity in psychosocially stressed male tree shrews – a validated animal model for depression (Fuchs, 2005) that is particularly appropriate for studying compounds with chronobiotic properties. In fact, psychosocially stressed tree shrews show several disturbances in the circadian rhythm of core body temperature and a sustained activation of the HPA system. Naïve adult male tree shrews were housed individually with a 12h light/12h dark cycle (lights on at 8:00 a.m.). For telemetric registration of core body temperature animals were implanted with radiotelemetric transmitters (Datascience Int., St. Paul, USA) and were allowed to recover for three weeks. HPA activity was monitored by measuring cortisol in the daily morning urine. Locomotor activity was registered daily for 1h between 4:30p.m. and 5:30p.m. by digital video recording. After a control week, animals were exposed to psychosocial stress daily during one week before the start of daily oral treatment with agomelatine or melatonin for 28 days (both at 40mg/kg and two hours before lights off); psychosocial stress continued throughout the 28-day treatment period. Chronic agomelatine treatment normalizes stress-induced decrease on body weight, increase in core body temperature (resetting of disturbed circadian functioning) and increase on HPA activity. Moreover, agomelatine counteracted the decrease in locomotor activity observed after stress. No effect of melatonin was observed on all parameters evaluated. These results show that, unlike melatonin, the joint action of agomelatine on MT₁, MT₂ and 5HT_2C receptors resynchronizes circadian rhythms in a model of depression. References: van Reeth O., Weibel L., Olivares E., Maccari S., Mocaër E., Turek F.W. (2001) Am J Physiol Regul Integr Comp Physiol; 280: R1582-R1591. Fuchs, E. (2005) CNS Spectr 10:182–189.