Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist,agomelatine, on the rat sleep–wake cycle architecture

Rationale  The novel antidepressant, agomelatine, behaves as an agonist at melatonin MT₁ and MT₂ receptors and as an antagonist at serotonin (5-HT)_2C receptors. In animal models and clinical trials, agomelatine displays antidepressant properties and re-synchronizes disrupted circadian rhythms. Objectives  The objectives of this study were to compare the influence of agomelatine upon sleep–wake states to the selective melatonin agonists, melatonin and ramelteon, and to the selective 5-HT_2C receptor antagonist, S32006. Methods  Rats were administered with vehicle, agomelatine, ramelteon, melatonin, or S32006, at the onset of either dark or light periods. Polygraphic recordings were performed and changes determined over 24 h, i.e., number and duration of sleep–wake episodes, latencies to rapid eye movement (REM) and slow-wave (SWS) sleep, power band spectra of the electroencephalogram (EEG), and circadian changes. Results  Administered at light phase onset, no changes were induced by agomelatine. In contrast, administered shortly before dark phase, agomelatine (10 and 40 mg/kg, per os) enhanced duration of REM and SWS sleep and decreased wake state for 3 h. Melatonin (10 mg/kg, per os) induced a transient enhancement in REM sleep followed by a reduction in REM and SWS sleep and an increase in waking. Ramelteon (10 mg/kg, per os) provoked a transient increase in REM sleep. Finally, S32006 (10 mg/kg, intraperitoneally), administered at dark phase onset, mimicked the increased SWS provoked by agomelatine, yet diminished REM sleep. Conclusions  Agomelatine possesses a distinctive EEG profile compared with melatonin, ramelteon, and S32006, possibly reflecting co-joint agonist and antagonist properties at MT₁/MT₂ and 5-HT_2C receptors, respectively. An erratum to this article can be found at     

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT<Subscript>2C</Subscript> receptors in Wistar rats

Agomelatine, an antidepressant with melatonin agonist and 5-HT_2C antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1-naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy-7-methoxynaphtalen-1-yl)ethyl]acetamide), have been assessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT_2C receptors and their effects on inositol phosphate production. These compounds were also tested for their ability to inhibit the penile erections induced by the 5-HT_2C receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT_2C receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175-induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT_2C receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175-induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agomelatine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT_2C receptor antagonist properties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine.Dr. Protais died in 2002     

Agomelatine,a melatonin agonist with antidepressant properties

Agomelatine (β-methyl-6-chloromelatonin), which is structurally homologous to melatonin, is a potent agonist of melatonin MT1 and MT2 receptors as well as an antagonist of serotonin 5-HT_2C receptors. Agomelatine appears to improve sleep without causing daytime sedation. It has not been found to be associated with sexual side effects and discontinuation symptoms. Three placebo-controlled trials, one of them a dose finding study and two of them pivotal trials, suggest that agomelatine is an antidepressant at doses of 25 – 50 mg/day. Agomelatine appears to be well tolerated, without sexual or cardiac adverse effects, weight gain or discontinuation syndromes. Animal studies suggest a possible neuroprotective action of agomelatine, although there are more data in favor of an anxiolytic effect. Substantially more research is needed to establish its role in the treatment of mood and circadian rhythm disorders.     

Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model

To confirm the antidepressant-like activity of agomelatine (S 20098), a melatonin agonist and 5-hydroxytryptamine2C antagonist, already reported in the chronic mild stress and forced swimming tests, the effects of agomelatine were investigated in the learned helplessness test and compared with those of imipramine, melatonin and a selective 5-hydroxytryptamine2C antagonist, SB-242 084. Agomelatine was administered for 5 days either once a day or twice a day, and the effects of pretreatment by a melatonin receptor antagonist, S 22153 (20 mg/kg/day), were studied. A deficit in avoidance learning was observed in helpless control animals. Agomelatine (10 mg/kg/day) administered once a day significantly reduced this deficit with an effect similar to that of imipramine. Effects of agomelatine were abolished by S 22153 pretreatment. Melatonin or SB-242 084 did not reduce the deficit of helpless control animals. These results confirm the antidepressant-like activity of agomelatine and suggest a role of melatonin receptors in its mechanism of action.     

Chronic agomelatine and fluoxetine induce antidepressant-like effects in H/Rouen mice, a genetic mouse model of depression

The novel antidepressant agomelatine behaves as an agonist at melatonergic MT₁ and MT₂ receptors and as an antagonist at serotonin 5-HT_2C receptors. This study investigated the effects of agomelatine and fluoxetine in a genetic model of depression called H/Rouen mice Male and female H/Rouen (helpless line) and NH/Rouen (nonhelpless line) mice, received once daily for 3 weeks agomelatine (10 and 50 mg/kg i.p.), fluoxetine (10 mg/kg i.p.) or vehicle. Immobility duration in the tail suspension test (TST) was assessed on day 1 (D1), day 8 (D8), day 15 (D15) and day 22 (D22). Locomotor activity in a novel environment was assessed on day 18 (D18) and anhedonia (2-bottle sucrose preference test) was considered after the end of chronic treatment, from days 22 to 25. Agomelatine (50 mg/kg) significantly reduced immobility at D15 (p < 0.01), and D22 (p < 0.001) in treated H/Rouen mice whereas agomelatine at 10 mg/kg did not induce a statistically significant change. Fluoxetine reduced immobility at D8 (p < 0.01), D15 (p < 0.001) and D22 (p < 0.001). Locomotor activity was unchanged in all treated groups as compared to vehicle groups. In the sucrose test, there was a significant decrease in sucrose preference in H/Rouen mice compared with NH/Rouen mice receiving vehicle. Both agomelatine doses (10 mg/kg (p = 0.05) and 50 mg/kg (p < 0.001) as well as fluoxetine (p < 0.001) significantly increased the sucrose preference in H/Rouen mice as compared with H/Rouen mice that had received vehicle. These data indicate that the novel antidepressant agomelatine has antidepressant-like properties in H/Rouen mice, a genetic model of depression.     

Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: a comparison to melatonin and to the 5-HT(2c) antagonist, S32006

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 50mg/kg), melatonin (10 and 50mg/kg), S32006 (0.16mg/kg to 10mg/kg) and the prototypical tricyclic antidepressant, imipramine (10mg/kg), were administered by intraperitoneal injection for 14days 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.     

The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats

Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT(2C) receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.     

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

The aim of the present study was to evaluate the effects of agomelatine, an antidepressant with melatonergic agonist and 5-HT_2C 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-HT_2C 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-HT_2C antagonist properties could be involved in these effects.     

Effect of 5-HT<Subscript>3</Subscript> antagonists and a 5-HT<Subscript>1A</Subscript> agonist on fluoxetine-induced conditioned gaping reactions in rats

Rationale  The effect of manipulation of the serotonin (5-HT) system on conditioned gaping (presumably reflective of nausea in rats) was evaluated. Objective  The potential of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (which produces nausea in the clinic), to produce conditioned gaping in rats and of the 5-HT₃ antagonists (ondansetron and palonosetron) and the 5-HT_1A autoreceptor agonist (8-OH-DPAT) to reverse this effect were evaluated. Materials and methods  In each of four experiments, rats received three pairings of intraorally delivered 17% sucrose solution and fluoxetine (0, 2, 10 or 20 mg/kg) and 72 h later were given a drug-free test trial. In experiment 2, rats were pretreated with the 5-HT₃ antagonists, ondansetron (0, 0.1 or 1.0 mg/kg) or the longer acting palonosetron (0.1 mg/kg), 30 min before each of three sucrose–fluoxetine (20 mg/kg) pairings. In experiment 3, rats were injected with palonosetron (0.1 mg/kg) 2 h before each of three sucrose–fluoxetine (20 mg/kg) or sucrose–lithium chloride (LiCl, 25 mg/kg) pairings. In experiment 4, rats were pretreated with the 5-HT_1A autoreceptor agonist, 8-OH-DPAT (DPAT, 0.1 mg/kg) 30 min before each of three sucrose–fluoxetine (20 mg/kg) pairings. Results  After two sucrose–fluoxetine pairings, the highest dose of fluoxetine tested (20 mg/kg) produced conditioned gaping reactions. These conditioned gaping reactions were prevented by pretreatment with DPAT, but not with the 5-HT₃ antagonists. On the other hand, palonosetron administered 2 h prior to sucrose–LiCl pairings attenuated conditioned gaping reactions. Conclusions  These results suggest that the conditioned nausea produced by SSRIs, but not LiCl, may be resistant to treatment with 5-HT₃ antagonists, but not 5-HT_1A autoreceptor agonists.     

Activation of Melatonin Receptors Reduces Relapse-Like Alcohol Consumption

Melatonin is an endogenous synchronizer of biological rhythms and a modulator of physiological functions and behaviors of all mammals. Reduced levels of melatonin and a delay of its nocturnal peak concentration have been found in alcohol-dependent patients and rats. Here we investigated whether the melatonergic system is a novel target to treat alcohol addiction. Male Wistar rats were subjected to long-term voluntary alcohol consumption with repeated abstinence phases. Circadian drinking rhythmicity and patterns were registered with high temporal resolution by a drinkometer system and analyzed by Fourier analysis. We examined potential antirelapse effect of the novel antidepressant drug agomelatine. Given that agomelatine is a potent MT1 and MT2 receptor agonist and a 5-HT_2C antagonist we also tested the effects of melatonin itself and the 5-HT_2C antagonist SB242084. All drugs reduced relapse-like drinking. Agomelatine and melatonin administered at the end of the light phase led to very similar changes on all measures of the post-abstinence drinking behavior, suggesting that effects of agomelatine on relapse-like behavior are mostly driven by its melatonergic activity. Both drugs caused a clear phase advance in the diurnal drinking pattern when compared with the control vehicle-treated group and a reduced frequency of approaches to alcohol bottles. Melatonin given at the onset of the light phase had no effect on the circadian phase and very small effects on alcohol consumption. We conclude that targeting the melatonergic system in alcohol-dependent individuals can induce a circadian phase advance, which may restore normal sleep architecture and reduce relapse behavior.     

Effect of agomelatine in the chronic mild stress model of depression in the rat.

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT(2C) antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine (both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration of agomelatine and melatonin was completely inhibited by an acute injection of the MT(1)/MT(2) antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT(2C) antagonist properties.     

Effects of acute and chronic treatment with fluoxetine on stress-induced hyperthermia in telemetered rats and mice

Preclinical and clinical evidence suggests that anxiolytic effects are observed after chronic administration of the selective serotonin reuptake inhibitor fluoxetine. In contrast, acute treatment may increase signs of anxiety. The present study examined the effects of acute and chronic administration of fluoxetine on a physiological measure of anxiety, stress-induced hyperthermia, in rats and mice using radiotelemetry to record core temperature and locomotor activity and ethologically relevant stressors to evoke the hyperthermic response. In both species, the benzodiazepine agonist chlordiazepoxide reduced stress-induced hyperthermia at doses (5 mg/kg i.p. rat, 10 mg/kg p.o. mouse) that had no significant effect on locomotor activity. Similarly, in both species, chronic (21 days) treatment with fluoxetine attenuated the hyperthermic response without significantly affecting locomotor activity. However, acute fluoxetine elicited species-specific effects. Thus in mice, stress-induced hyperthermia and activity were unaffected by fluoxetine (20 mg/kg p.o.) consistent with a lack of anxiolytic or anxiogenic activity. In contrast, in rats, fluoxetine (10 mg/kg i.p.) caused a significant baseline hypothermia in the absence of stress, confounding further interpretation. In conclusion, stress-induced hyperthermia in mice was unaffected by acute treatment and significantly reduced by chronic treatment with fluoxetine. However, in rats chronic administration of fluoxetine significantly reduced stress-induced hyperthermia while the effects of acute treatment were confounded by a decrease in body temperature in the absence of stress. Together, these observations support the view that chronic administration of fluoxetine is anxiolytic; however, the stress-induced hyperthermia assay does not reveal anxiogenic effects of acute administration of fluoxetine in rats or mice.     

Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test

BackgroundSeveral clinical reports have postulated a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants in treatment-resistant depression.MethodsThe present study aimed to examine the effect of treatment with fluoxetine or mirtazapine, given separately or jointly with risperidone, on active behavior and plasma corticosterone level in male Wistar rats subjected to the forced swim test (FST).ResultsThe obtained results showed that fluoxetine (5 mg/kg), mirtazapine (5 and 10 mg/kg) or risperidone (0.05 and 0.1 mg/kg) did not change the active behavior of rats in the FST. However, co-treatment with fluoxetine (10 mg/kg) and risperidone (0.1 mg/kg) induced an antidepressant-like effect in that test because it significantly increased the swimming time and decreased the immobility time, while combined treatment with mirtazapine at 5 and 10 mg/kg and risperidone at 0.05 and 0.1 mg/kg evoked a significant increase in the swimming time and also climbing, and decreased the immobility time. WAY 100635 (a 5-HT_1a receptor antagonist) at a dose of 0.1 mg/kg inhibited the antidepressant-like effect induced by co-administration of fluoxetine or mirtazapine and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined treatment with fluoxetine or mirtazapine and risperidone failed to enhance the exploratory activity of rats. Co-treatment with fluoxetine or mirtazapine and risperidone did not reduce the stress-induced increase in plasma corticosterone concentration in animals subjected to the FST.ConclusionThe obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of fluoxetine and mirtazapine in the FST (but does not normalize the stress-induced increase in corticosterone level in these rats), and that 5-HT_1a receptors may play some role in these effects.     

Agomelatine but not melatonin improves fatigue perception: A longitudinal proof-of-concept study

Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep–wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50 mg u.i.d. with sustained release melatonin 10 mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study. Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.     

Preclinical evaluation of the reinforcing and discriminative stimulus effects of agomelatine (S-20098), a melatonin agonist

 Agomelatine (S-20098), an analog of melatonin, has shown promise as a chronobiotic in animal models of sleep phase disorders and is being developed for clinical use. Previous research has shown that the pharmacological profile of melatonin-like drugs overlaps that of γ-amino butyric acid (GABA) agonists. Given the potential of drugs within the latter class for recreational abuse in humans, evaluation of this potential for melatonin analogs that target similar therapeutic indications is important. In the present study, agomelatine was tested in animal models of the subjective and reinforcing effects of CNS depressant drugs; i.e., diazepam discrimination in rats and IV methohexital self-administration in rhesus monkeys, respectively. Neither agomelatine nor melatonin substituted for diazepam in rats trained to discriminate 2.5 mg/kg diazepam from vehicle. Further, agomelatine was not self-administered by rhesus monkeys. These results suggest that agomelatine would not produce diazepam-like intoxication in humans, nor would it likely be subject to abuse. Received: 26 March 1998 / Final version: 27 May 1998     

Effect of agomelatine and its interaction with the daily corticosterone rhythm on progenitor cell proliferation in the dentate gyrus of the adult rat

Agomelatine, a novel melatonin analogue and anti-depressant that acts as an agonist on melatonin receptors 1 and 2 and as an antagonist at the 5HT2C receptor, was tested for its effects on cell proliferation in the dentate gyrus of the adult rat hippocampus under intact and flattened corticosterone rhythm conditions. Agomelatine stimulated mitosis rates in the intact male rat. Flattening the daily corticosterone rhythm by inserting a subcutaneous pellet of this steroid prevented the action of agomelatine. However, adding a daily injection of corticosterone at CT1200 to rats with implanted corticosterone pellets failed to restore agomelatine’s efficacy on cell proliferation. The 5HT2C receptor antagonist SB242084 stimulated progenitor cell proliferation in the dentate gyrus, while a 5HT2C agonist (RO600175) had no effect on cell proliferation alone, but counteracted that of agomelatine. These results suggest that agomelatine, a new anti-depressant, can stimulate progenitor cell mitosis in the dentate gyrus. Its action requires an intact diurnal corticosterone rhythm. The action of agomelatine on neurogenesis is likely to reside in its antagonism of the 5HT2C receptor, and suggests a mechanism distinct from that of fluoxetine, another anti-depressant, which, as previous work shows, acts through the 5HT1A receptor, but whose action is also blocked by a flattened corticosterone rhythm.     

Differential effects of the novel antidepressant agomelatine (S 20098) versus fluoxetine on 5-HT1A receptors in the rat brain

Agomelatine (S 20098) is a novel antidepressant drug with melatonin receptor agonist and 5-HT(2C) receptor antagonist properties, but actual mechanisms underlying its antidepressant action are unknown. Because functional desensitization of 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) occurs after chronic administration of several classes of antidepressants, we investigated whether this adaptive change could also be induced by agomelatine. Neither acute nor chronic treatment with agomelatine (10 mg/kg i.p. for 14 days or 50 mg/kg i.p. for 21 days) changed the density of 5-HT(1A) receptors and their coupling with G proteins in the DRN and the hippocampus in rats. Moreover, these treatments did not affect the basal electrophysiological characteristics and the responses to 5-HT(1A) receptor stimulation of DRN and hippocampal neurons in brain slices. Parallel experiments with melatonin (10 mg/kg i.p. for 14 days) and fluoxetine (5 mg/kg i.p. for 14 days) as reference compounds showed that the former was unable to affect 5-HT(1A) receptors whereas the latter decreased both the 5-HT(1A) receptor-mediated [(35)S]GTP-gamma-S binding and the potency of ipsapirone, a 5-HT(1A) receptor agonist, to inhibit neuronal firing in the DRN. These data indicate that the antidepressant action of agomelatine is not mediated through the same mechanisms as SSRIs or tricyclics.     

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

Rationale

Agomelatine is described as a novel and clinical effective antidepressant drug with melatonergic (MT₁/MT₂) agonist and 5-HT_2C receptor antagonist properties. Previous studies suggest that modulation of neuronal plasticity and microtubule dynamics may be involved in the treatment of depression.

Objective

The present study investigated the effects of agomelatine on microtubular, synaptic and brain-derived neurotrophic factor (BDNF) proteins in selected rat brain regions.

Methods

Adult male rats received agomelatine (40?mg/kg?i.p.) once a day for 22?days. The pro-cognitive effect of agomelatine was tested in the novel object recognition task and antidepressant activity in the forced swimming test. Microtubule dynamics markers, microtubule-associated protein type 2 (MAP-2), phosphorylated MAP-2, synaptic markers [synaptophysin, postsynaptic density-95 (PSD-95) and spinophilin] and BDNF were measured by Western blot in the hippocampus, amygdala and prefrontal cortex (PFC).

Results

Agomelatine exerted pro-cognitive and antidepressant activity and induced molecular changes in the brain areas examined. Agomelatine enhanced microtubule dynamics in the hippocampus and to a higher magnitude in the amygdala. By contrast, in the PFC, a decrease in microtubule dynamics was observed. Spinophilin (dendritic spines marker) was decreased, and BDNF increased in the hippocampus. Synaptophysin (presynaptic) and spinophilin were increased in the PFC and amygdala, while PSD-95 (postsynaptic marker) was increased in the amygdala, consistent with the phenomena of synaptic remodelling.

Conclusions

Agomelatine modulates cytoskeletal microtubule dynamics and synaptic markers. This may play a role in its pharmacological behavioural effects and may result from the melatonergic agonist and 5-HT_2C antagonist properties of the compound.     

Functional subsensitivity of 5-HT2A and 5-HT2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT2A/2C receptor antagonists

 In the present study, we investigated the duration of attenuation of the temperature increases produced by (±) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) which followed pretreatment with four serotonin (5-HT) antagonists; metergoline, mesulergine, mianserin and ritanserin. The duration of attenuation of m-CPP-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for the 5 mg/kg doses of both mianserin and metergoline and more than 2 days for the 5 mg/kg dose of mesulergine. The duration of attenuation of DOI-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for mianserin, more than 2 days for the 5 mg/kg dose of metergoline and more than 4 days for mesulergine. Daily administration of a low (1.0 mg/kg per day) dose of ritanserin for 14 days led to an attenuation of the temperature increases produced by m-CPP given 24 h after the last dose of ritanserin, but did not cause a similar desensitization of DOI-induced hyperthermia. On the other hand, daily administration of both low (1.0 mg/kg per day) and high (5.0 mg/kg per day) doses of mianserin for 14 days caused desensitization of DOI-induced hyperthermia but did not cause desensitization of m-CPP-induced hyperthermia when these agonists were administered 48 h after the last dose of mianserin. These findings demonstrate functional subsensitivity of both 5-HT_2A and 5-HT_2C receptors mediating hyperthermia following both acute and chronic administration of 5-HT_2A/5-HT_2C receptor antagonists; some differences in time course and in responses to individual antagonists at 5-HT_2A versus 5-HT_2C sites were also observed. Received: 14 June 1996 / Final version: 28 August 1996