Anxiolytic-like action of the antidepressant agomelatine (S 20098) after a social defeat requires the integrity of the SCN

Abstract

In rats, social defeat by an aggressive opponent induces a state of anxiety, shown by a decrease in time spent on active explorative behaviour, an increase in immobility, a clear decrease in frequency of all active behavioural parameters (enhanced passivity). We tested the hypothesis whether acute or sub-chronic agomelatine would antagonize the negative consequences of a social defeat. As many chronobiological actions of melatonin and its receptor agonist agomelatine require the integrity of the suprachiasmatic nuclei (SCN), we examined whether the anxiolytic-like action of agomelatine 1 day after a social defeat is still present in SCN-lesioned rats. Sub-chronic administration of agomelatine caused a clear reduction of the social defeat induced behavioural consequences. A single agomelatine injection prior to the post-defeat test was less effective and a single melatonin injection was hardly effective. SCN lesion did not affect the anxiety reaction after a social defeat. Thus, sub-chronic agomelatine treatment or a single agomelatine injection reduced a state of anxiety and passivity caused by asocial defeat. The defeat-induced behavioural changes do not depend on the SCN but agomelatine showed its anxiolytic action only in sham-lesioned animals, which indicates that the anxiolytic-like action of agomelatine requires the integrity of the SCN. Mechanisms sustaining this activity are discussed.

The role of the circadian clock in animal models of mood disorders.

“…However, there is only limited evidence that SCNx animals suffer disturbed mood regulation. SCNx rats show less immobility in the forced swim test, but no impact on behavior in the social defeat paradigm (Arushanian & Popov, 1994;Tataroglu, Aksoy, Yilmaz, & Canbeyli, 2004;Tuma, Strubbe, Mocaer, & Koolhaas, 2005).…”

Circadian genes, rhythms and the biology of mood disorders

“…However, a study by Tuma et al found that SCN lesions had no effect on the depression and anxiety-like behaviors that are displayed after repeated bouts of social defeat (Tuma et al, 2005). The SCN does appear to play some role in this task, however, since the antidepressant, agomelatine, which is normally effective in reducing the depression and anxiety-like behavior following social defeat, was not effective in the SCN lesioned animals (Tuma et al, 2005). Thus the SCN might be needed to produce the therapeutic effects of agomelatine.…”

Agomelatine, melatonin and depressive disorder

“…Bilateral lesions of the SCN in rats were found to have an antidepressantlike effect in the forced swim test: decreased immobility time and greater swimming time [19]. On the other hand, in one study SCN lesions did not offer protection against 'depression-like behaviour' in the social defeat paradigm [20]. Thus, the SCN may be important for mediating the effects of antidepressants and possibly in depression/ depressogenic effects.…”