Memory facilitating effects of agomelatine in the novel object recognition memory paradigm in the rat

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Abstract

The aim of the present study was to evaluate the effects of agomelatine, an antidepressant with melatonergic agonist and 5-HT2C antagonist properties, in the rat novel object recognition (NOR) task, a model of short-term episodic memory. To assess the potential involvement of its chronobiotic activity, single intraperitoneal administration of agomelatine and NOR testing were performed either in the evening or in the morning. In both conditions, using a 24 h retention interval, vehicle-treated rats did not discriminate between the novel and the familiar object (recognition index was not different from chance performance) while object memory performance of rats treated with agomelatine either in the evening (10 and 40 mg/kg) or in the morning (2.5, 10, and 40 mg/kg) was significantly improved. Moreover, the selective 5-HT2C antagonist SB 242,084 (0.63, 2.5, and 10 mg/kg) and melatonin (2.5, 10, and 40 mg/kg) displayed also memory facilitating effects in both administration conditions. Finally, thioperamide used as positive reference compound to validate the experimental conditions, demonstrated a memory facilitating effect. In conclusion, agomelatine was shown to possess memory facilitating effects in the rat NOR task and both melatonergic agonist and 5-HT2C antagonist properties could be involved in these effects.

Research Highlights

► Agomelatine displays memory facilitating properties. ► Agomelatine improves memory performance in the NOR task in the rat. ► Melatonergic agonist and 5-HT2C antagonist properties are important for this effect.

Introduction

Agomelatine is a novel antidepressant acting as a potent agonist of melatonergic MT1 and MT2 receptors (Ying et al., 1996, Yous et al., 1992) and an antagonist of the 5-HT2C receptors (Millan et al., 2003). Agomelatine has demonstrated a clear efficacy as an antidepressant in clinical trials (Kennedy and Emsey, 2006, Lôo et al., 2002, Olie and Kasper, 2007, Kennedy, 2009, Kennedy and Rizvi, 2010) with fewer side-effects than more classical antidepressants (Kasper and Hamon, 2009, Kennedy and Rizvi, 2010).

The chronobiotic activity of agomelatine may contribute to its efficacy in treating patients with major depressive disorder (MDD), the disruption of internal circadian rhythms being one important feature of depression (Wehr and Wirz-Justice, 1982). Indeed, in preclinical studies, agomelatine is able to re-synchronise disrupted circadian rhythms (Armstrong et al., 1993, Martinet et al., 1996, Redman et al., 1995, Van Reeth et al., 1997). After chronic treatment, agomelatine dose-dependently restored the phase shifting response to a dark pulse (Van Reeth et al., 2001) and accelerated the resynchronization of the rhythm to new light–dark cycle in aged hamsters by 25% (Weibel et al., 2000). The re-entraining activity of agomelatine is linked to its receptor profile, and a clear relation between plasma agomelatine concentration and entrainment has been demonstrated (Martinet et al., 1996).

In preclinical studies, agomelatine has been shown to display antidepressant and anxiolytic properties in different experimental models: antidepressant-like effects of agomelatine have been shown in the forced swimming test (Bourin et al., 2004), the chronic mild stress model (Papp et al., 2003), the learned helplessness model (Bertaina-Anglade et al., 2006a) and a transgenic mouse model with low glucocorticoid receptor function (Barden et al., 2005); anxiolytic-like effects of agomelatine have been described in rats subjected to the social interaction test and the Vogel conflict procedure (Millan et al., 2005), the elevated plus-maze test (Papp et al., 2006) and the social defeat model (Tuma et al., 2005).

Preclinical (Henningsen et al., 2009, Kalueff and Murphy, 2007) and clinical (Baune et al., 2008, Hammar and Ardal, 2009) data suggest that depressive disorders are often associated with cognitive impairment in different cognitive domains such as executive function, working memory and attention. In order to evaluate the effects of agomelatine on memory, we initially tested the compound in a reference memory model, the T maze left–right spatial discrimination test. In this model, a single administration of agomelatine (1 and 10 mg/kg) improved discrimination performance of the mice, the effect being more intense when agomelatine was administered in the evening compared to a morning administration (Jaffard et al., 1993). Besides, recent data suggests that, following chronic treatment, agomelatine (10 mg/kg) is able to reverse a stress-induced spatial memory impairment in the rat assessed in the radial-arm water maze (Conboy et al., 2009).

In the present study, the effects of agomelatine were assessed in the novel object recognition (NOR) task, a simple non-rewarded recognition memory test (Ennaceur and Delacour, 1988). The NOR task is being increasingly used as an experimental tool in assessing drug effects on memory and can also be used in safety pharmacology to identify pro-amnesic properties of new drugs (Bertaina-Anglade et al., 2006b). This paradigm is sensitive to pharmacological manipulations e.g. phencyclidine (PCP) challenge (Grayson et al., 2007) or cholinergic hypofunction (Bartolini et al., 1996) and to ageing (Platano et al., 2008, Scali et al., 1997). This task is based on the natural propensity of rats to explore novelty in their environment (Dere et al., 2007).

More specifically, rodents are able to discriminate between a novel and a previously seen (i.e. familiar) object. During the first (learning) trial, rats are exposed to two identical objects. Then, after an inter-trial interval (ITI), one of the previously explored objects now familiar is introduced during a test trial, together with a novel object. At short ITIs, rats can discriminate between the two objects, spending more time exploring the novel object than the familiar one. NOR is sensitive to delay intervals (Ennaceur and Delacour, 1988, Ennaceur and Meliani, 1992, Pitsikas and Sakellaridis, 2005). With longer ITI (24 h), animals are unable to discriminate between the familiar and a novel object, spending the same amount of time with the two objects. This situation of forgetting is exploited to screen for memory facilitating drugs.

The NOR test has been widely used as a pre-clinical test to investigate the memory enhancing effects of acetylcholinesterase inhibitors such as donepezil (Prickaerts et al., 2005) and galantamine (de Bruin and Pouzet, 2006) used as treatments in Alzheimer's disease. Besides, histamine H3 receptor antagonists have been demonstrated to improve learning and memory in various experimental models in rodents likely via an increase of the central histaminergic tone and histaminergic–cholinergic interactions (see Giovannini et al., 1999, Vohora, 2004). In the NOR task, thioperamide, “prototype” of the histamine H3 receptor antagonists, improved long-term (24 h) object recognition memory (Giovannini et al., 1999, Orsetti et al., 2001). Thus, thioperamide was chosen as reference compound to validate the NOR experimental conditions used in this study.

Presently, as regards the mechanistic profile of action of agomelatine, the effects of a single administration of agomelatine in the NOR model were compared to those of a similar treatment with melatonin and a selective 5-HT2C receptor antagonist (SB 242,084). Furthermore, administration of the compounds was performed at two different moments across the daily cycle. Indeed, significant diurnal variations of melatonin receptor agonist activity have been reported for melatonin on exploration and anxiety (Golombek et al., 1993). Accordingly, agomelatine displays a chronobiotic activity after an evening treatment but is devoid of any chronobiotic effect after a morning administration (Van Reeth et al., 1997). Thus, in the present NOR test, the effects of agomelatine, melatonin and SB 242,084 were assessed in the evening (within 2 h before the beginning of the dark phase of the 12-h light/dark cycle) and in the morning (within 3 h after the end of the dark phase).

Thus, the present study was designed to assess 1) the effects of agomelatine in the NOR paradigm and 2) if agomelatine is shown to be effective in the test, the participation of its melatonergic agonist and 5-HT2C antagonist properties to these effects and the potential link with its chronobiotic activity.

Section snippets

Animals

Experiments were carried out using male Sprague–Dawley rats (Centre d'élevage Janvier, France, n = 12–15 per group) weighing 220–300 g (6 weeks old). The animals were housed 2 to 4 individuals per cage, in a regulated environment (22 ± 2 °C, 55 ± 10% relative humidity, 12–12 h light/dark cycle, light on at 6:00 am in experiments 1 and 2 and at 8:00 am in experiment 3) with free access to food and water. The acclimation period before the beginning of the experiments was 5 days.

After testing was completed,

Learning phase: Duration of the learning trial

In each experiment, statistical analyses performed on the duration of the learning trial showed no significant difference between-groups (Table 1). These results suggest that animals have been correctly randomised across groups in the different experiments.

Experiment 1: Effects of agomelatine and SB 242,084 in the NOR task with evening administration

The comparison of the recognition index to chance performance showed that RI of rats treated with agomelatine at 10 and 40 mg/kg (RI = 28 ± 6% and 23 ± 4%, respectively) or with SB 242,084 at 0.63, 2.5 and 10 mg/kg (RI = 24 ± 7%, 17 ± 4% and 20 ± 6%,

Discussion

The present study demonstrates that agomelatine (2.5, 10 and 40 mg/kg), melatonin (2.5, 10 and 40 mg/kg) and SB 242,084 (0.63, 2.5 and 10 mg/kg) following a single morning or evening i.p. administration, can enhance object recognition memory with a 24 h retention delay, a situation in which memory performance is reduced in control rats. In order to validate our experimental conditions, the histamine H3 receptor antagonist thioperamide was used as a reference compound. In the present NOR test and as

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