Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: A comparison to melatonin and to the 5-HT_2c antagonist, S32006

Abstract

The novel melatonergic agonist/5-HT_2C 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-HT_2C 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-HT_2C 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.

Introduction

Depression is a chronic, recurrent disorder (Hirschfeld and Schatzberg, 1994, Millan, 2006). While two thirds of depressed patients may respond to initial antidepressant therapy, 10-15% will remain resistant to current treatments (Burrows et al., 1994). Non-compliance with treatment is a short coming of current medications (Zajecka, 2000). Most pharmacological interventions focus on altering serotonergic and noradrenergic neurotransmission (Norman and Olver, 2010, Olver et al., 2001). Novel approaches to the treatment of depression are needed to address some of the apparent problems of current agents (Möller, 2008, Norman, 2006).

Disruption to circadian rhythms has been proposed as an aetiological factor in depressive disorders (Bunney and Potkin, 2008, Monteleone and Maj, 2008, Norman, 2010). Cardinal features of depression (e.g., sleep disturbances, alterations in diurnal body temperature, motor activity) favour a circadian hypothesis (Duncan, 1996, Parry et al., 1989). This is supported by a positive association between the degree of disruption in the timing of sleep-wake cycles and severity of depressive symptoms (Emens et al., 2009). Re-entrainment of disturbed circadian rhythms has been found to be useful in the treatment of some depressive states (Lewy and Sack, 1989, Lewy et al., 2006).

Agomelatine is an agonist at the melatonergic MT₁ and MT₂ receptor (Audinot et al., 2003), and an antagonist at 5 HT_2C receptors (Millan et al., 2003, Millan et al., 2010). It can re-synchronise experimentally disrupted circadian rhythms (Redman et al., 1995). Agomelatine restores the circadian rest-activity cycle in depressed patients (Kasper et al., 2010). Agomelatine increases noradrenaline and dopamine in the frontal cortex, without modifications of serotonin levels (Millan et al., 2003, Millan et al., 2005).

In pre-clinical tests agomelatine displays activity indicative of antidepressant potential under chronic conditions. Thus in the forced swim test (FST) (Bourin et al., 2004), the learned helplessness task (Bertaina-Anglade et al., 2006), the chronic mild stress paradigm (Papp et al., 2003) and in a transgenic mouse model (Barden et al., 2005, Païzanis et al., 2010) agomelatine is active. Clinical trials have confirmed antidepressant efficacy superior to placebo (Goodwin et al., 2009, Loo et al., 2002) and at least comparable to other antidepressants (e.g., Hale et al., 2010, Kasper et al., 2010). Preclinical studies have suggested a potential synergy between the melatonin agonist and the 5-HT_2C antagonist properties contributing to the antidepressant activity (Bertaina-Anglade et al., 2006, De Bodinat et al., 2010, Papp et al., 2003).

This study examined the potential antidepressant activity of agomelatine compared to S32006, a 5-HT_2C antagonist (Dekeyne et al., 2008) and melatonin using the olfactory bulbectomised rat model of depression. The bulbectomy model is recognised to possess high face and predictive validity. Removal of the bulbs results in behavioural changes (e.g., irritability, impaired learning, hyperactivity in an open field) (Cairncross et al., 1979, Kelly et al., 1996)), relevant to several major clinical dimensions of depression (Marazziti et al., 2010, Millan, 2006, Song and Leonard, 1995). Changes in immune function have also been reported (Kelly et al., 1997). Behavioural changes can be reversed by chronic treatment with antidepressants (Jancsar and Leonard, 1984a, Jancsar and Leonard, 1984b, McGrath and Norman, 1998).