Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models

Abstract

Aim: To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice. Methods: In the learned helplessness test (LH), Neu-P11 or melatonin (25-100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25-100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25-100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed. Results: In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon. Conclusion:The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.

Agomelatine (S20098) modulates the expression of cytoskeletal microtubular proteins, synaptic markers and BDNF in the rat hippocampus, amygdala and PFC

“…decreased immobility in the FST (Micale et al 2006) as well as single and a 5-day (once a day) administration of the novel melatonin agonist NEU-P11 (25-100 mg/kg i.p.) (Tian et al 2010), but one study showed no effects of chronic (14 days in drinking water) administration of melatonin (4 μg/ml) (Brotto et al 2000). Similarly, results obtained with a single administration of the 5-HT 2C antagonist molecules SB206533 (Cryan and Lucki 2000) or SB242084 (Calcagno et al 2009) showed no effects in the rat FST, while the highly selective ↑ significant increase, ↓ significant decrease, ↔ no changes, : tendency to increase, : tendency to decrease, LMA locomotor activity, NOR novel object recognition task, FST forced swimming test.…”

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

“…Experimental studies have revealed that melatonin exerts a modest activity in different tests for anxiety in rodents ( (Golombek et al, 1993;Loiseau et al, 2006;Papp et al, 2006, Tian et al, 2010, suggesting a primary role for melatonin receptors in mediating the chronobiotic properties of the hormone.…”

“…In contrast, acute administration of melatonin in the morning was found to be ineffective in most anxiety tests (Golombek et al, 1993;Loiseau et al, 2006;Millan et al, 2005;Papp et al, 2006). However, agomelatine and the melatonin agonist Neu-P11 exhibited potent anxiolytic effects independent of the timing of administration (Millan et al, 2005;Papp et al, 2006, Tian et al, 2010. Although these new drugs were shown to have slightly weaker effects than the classical anxiolytics diazepam and buspirone (Tian et al, 2010), they do not produce sedation (Papp et al, 2006).…”

“…However, agomelatine and the melatonin agonist Neu-P11 exhibited potent anxiolytic effects independent of the timing of administration (Millan et al, 2005;Papp et al, 2006, Tian et al, 2010. Although these new drugs were shown to have slightly weaker effects than the classical anxiolytics diazepam and buspirone (Tian et al, 2010), they do not produce sedation (Papp et al, 2006). The melatonin antagonist S22153 was shown to block the activities of melatonin and agomelatine when the latter were administered in the evening but not in the morning (Papp et al, 2006), confirming 9 the assumption that the anxiolytic effects of the two drugs are mediated by melatonin receptors.…”

“…The melatonin antagonist S22153 was shown to block the activities of melatonin and agomelatine when the latter were administered in the evening but not in the morning (Papp et al, 2006), confirming 9 the assumption that the anxiolytic effects of the two drugs are mediated by melatonin receptors. However, the lack of a time-dependent effect on anxiety with agomelatine suggests a role for 5-HT2C receptor antagonism, whereas the lack of a chronobiotic activity for Neu-P11 might be due to its interaction with GABAergic (Laudon et al, 2008) or 5-HT (Tian et al, 2010) pathways. Agomelatine's dual action on melatoninergic and serotoninergic components determines a broader anxiolytic efficacy and lack of chronobiotic dependence compared with melatonin.…”