Abstract
Agomelatine behaves both as a potent agonist at melatonin MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic and 5-hydroxytryptaminergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in hippocampal proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodelling, glutamate signalling) and key targets (early genes, kinases). The present review focuses on the pharmacological properties of this novel antidepressant. Its mechanism of action, strikingly different from that of conventional classes of antidepressants, opens perspectives towards a better understanding of the physiopathological bases underlying depression.
Keywords: agomelatine, antidepressant, melatonin receptors, 5-HT2C receptors
Introduction
Strong links exist between abnormal patterns of circadian rhythms and some of the most characteristic symptoms of affective disorders, including unipolar and bipolar depression (Wirz-Justice and Van den Hoofdakker, 1999; McClung, 2007; Turek, 2007). These symptoms include delayed sleep onset, non-restful sleep, early-morning wakening, blunting or reversal of the normal morning peaks in subjective energy, mood or alertness, and daytime fatigue (Germain and Kupfer, 2008). Hence, the human circadian system holds possible important clues regarding the aetiology and the treatment of affective disorders. Actually, circadian patterns of gene expression are disrupted in major depressive disorders (Li et al., 2013). Therefore, an innovative approach to improve the treatment of depression in patients with abnormal circadian rhythmicity may include the administration of circadian phase-shifting agents. The goal of such treatment is not only to restore sleep–wake patterns (Guardiola-Lemaitre and Quera-Salva, 2011), but also to resynchronize the circadian system and its link with the external environment. This way of thinking lead to the discovery of agomelatine (Adam et al., 1992; Yous et al., 1992), a compound that combines melatonin receptor (see Alexander et al., 2013a) agonism with 5-HT2C receptor antagonism (Delagrange and Guardiola-Lemaitre, 1997).
The mode of action of agomelatine is obviously different from that of other available antidepressants. The psychotropic effects of agomelatine are caused by the synergy between the melatonergic and 5-HT2C receptor properties of the compound (Racagni et al., 2011). Both animal experimental and human clinical data establish that this innovative pharmacology translates into a clinical benefit (Kennedy et al., 2008; Kennedy and Rizvi, 2010; Martinotti et al., 2012). Critical analyses of the available clinical studies with agomelatine have appeared elsewhere (de Bodinat et al., 2010; Kennedy and Rizvi, 2010; Hickie and Rogers, 2011). Likewise, the history of the discovery and development of agomelatine have been summarized elsewhere (de Bodinat et al., 2010). In the present review, we aim to provide a comprehensive inventory of the current knowledge of the cellular actions and the pharmacological properties of agomelatine in animal models, which predict clinical antidepressant efficacy.
Binding properties
Using an enzymatic assay to measure cAMP (as no cloned melatonin receptors were available at that time), it was first demonstrated that, similar to melatonin, micromolar concentrations of agomelatine inhibit the in vitro production of cAMP by cells of the pars tuberalis of the sheep. In addition, agomelatine completely displaced 2-iodo-melatonin from its main binding sites in the pars tuberalis (at 10−8M) and in the suprachiasmatic nucleus (SCN) of the hypothalamus (at 10−10M) (Bonnefond et al., 1993). Binding assays with transfected cells and native tissues confirmed that agomelatine has a high affinity for human melatonin MT1 and MT2 receptors (Ki ∼10−10M) and behaves in vitro as a melatonergic agonist (Audinot et al., 2003).
That the mechanism of action of agomelatine differs from that of other classes of antidepressants is exemplified by the finding that it has no affinity (Ki > 10 μM) for most screened receptors, including adenosine, adrenoceptors, dopamine (DA), GABA, muscarinic, nicotinic, histamine, excitatory amino acid, benzodiazepine and sigma receptors, as well as sodium, potassium and calcium channels. Similarly, most 5-HT receptors are not recognized by the compound, which has only some affinity for the 5-HT2 receptor family. Indeed, agomelatine binds with 5-HT2C receptor (pKi = 6.2) and interacts also with cloned, human 5-HT2B receptors (pKi = 6.6), but shows negligible affinity at 5-HT2A receptors (pKi < 6) (Millan et al., 2003). That agomelatine acts as an antagonist at 5-HT2C and HT2B receptor subtypes has been established in transfected cells expressing human 5-HT2C receptors, in which the compound antagonizes both the 5-HT-induced specific binding of [35S]-GTP-γ-S to G-proteins specifically coupled to the receptors, and the 5-HT-induced activation of PLC.
Agomelatine behaved as an antagonist at human 5-HT2B receptors in an assay of [3H]-phosphatidylinositol depletion, but the functional significance of this activity to the central action of the compound remains unclear. Several findings suggest that 5-HT2B receptors play a functional role in the periphery and in the brain (Brea et al., 2010) and predict that no noxious and perhaps even beneficial effects of agomelatine may be expected in humans based on 5-HT2B receptor antagonist properties. For example, 5-HT2B receptor antagonists can reduce arterial blood pressure in hypertensive rats (Watts and Fink, 1999), prevent cardiac hypertrophy in mice (Jaffre et al., 2004; Monassier et al., 2008) and improve neuropathic, visceral pain and hyperalgesia in rodents (Aira et al., 2010; O'Mahony et al., 2010; Lin et al., 2011; Cervantes-Duran et al., 2012). Agomelatine does not interact with classical targets of antidepressant drugs, namely MAO A and B and the transporters responsible for the re-uptake of 5-HT, NA or DA (de Bodinat et al., 2010). In line with these data, acute or chronic treatments with agomelatine (10 or 50 mg·kg−1·day−1 i.p. for up to 3 weeks) did not affect the extracellular levels of 5-HT in the frontal cortex of adult rats (Millan et al., 2003). Moreover, chronic agomelatine administration does not down-regulate 5-HT1A receptors (Hanoun et al., 2004) and does not affect extracellular levels of 5-HT (Millan et al., 2005). Actually, owing to the absence of facilitatory influence of agomelatine on central and/or peripheral actions of 5-HT, it does not cause, the major adverse effects of the conventional antidepressants [e.g. gastrointestinal disorders, sleep disturbances (e.g. rapid eye movement – REM – sleep inhibition) and sexual dysfunctions (de Bodinat et al., 2010) ].
Although the affinity of agomelatine at 5-HT2C receptors is about 1000-fold lower than that at MT1 and MT2 receptors, the functional 5-HT2C antagonistic property of agomelatine has been established in vivo at antidepressant doses (10–50 mg·kg−1) (Chagraoui et al., 2003). A MRI study in rats shows that agomelatine in the same dose range (10–40 mg·kg−1) blocks central 5-HT2C receptors in vivo within a broad range of corticolimbic structures, including the hippocampus (Linnik et al., 2009).
The 5-HT2C receptors are the only known GPCRs to be subjected to RNA editing, a mechanism that can generate multiple variants of a particular gene, thereby producing 5-HT2C receptor isoforms with various properties (i.e. affinity, coupling and constitutive activity) (Werry et al., 2008). In this context, the interaction of agomelatine with this receptor subtype may be more complex than initially thought as the compound may be a more potent antagonist for certain 5-HT2C isoforms. Thus, while agomelatine behaves as an antagonist at human edited 5-HT2C receptors, it acts as a neutral antagonist at unedited and constitutively active 5-HT2C receptors (Millan et al., 2011b). The interaction of agomelatine has been examined with unedited human (h) 5-HT2C(INI) receptors expressed in HEK-293 cells, and with native, 5-HT2C receptors of mouse cortical neurons, two populations of receptors known to display constitutive activity. Agomelatine behaves as a neutral antagonist at constitutively active h5-HT2C(INI) receptors and native, cerebral 5-HT2C receptors. In fact, agomelatine does not affect activity of GPCRs, but rather normalizes signalling at 5-HT2C sites by blocking the actions both of agonists and of inverse agonists, thereby returning activity to baseline value rather than suppressing it (Millan et al., 2011b).
It is difficult to extrapolate from cellular findings, but inasmuch as 5-HT2C receptors in the brain are constitutively active, the neutral antagonist profile of agomelatine may be important for at least two reasons. Firstly, it may explain why agomelatine does not markedly accelerate subcortical versus fronto-cortical dopaminergic transmission. Indeed, agomelatine can increase the extracellular levels of dopamine and NA in the frontal cortex, whereas no change in dopamine level is seen in the nucleus accumbens or the striatum (Millan et al., 2003). Accordingly, the acute administration of agomelatine induces a 50% increase in the firing rate of noradrenergic neurons in the locus coeruleus (LC), no changes in the firing pattern of dopaminergic neurons in the ventral tegmental area (VTA) but an increase in spontaneously active cells, and no effect on 5-hydroxytryptaminergic firing activity in the dorsal raphé nuclei (DRN). The agomelatine-induced increase in the number of spontaneously active dopaminergic neurons is, at least in part, mediated by melatonin receptors as it is antagonized by a single administration of the MT1/MT2 antagonist S 22153 (Chenu et al., 2013). These effects are in accord with the neutral antagonist property of agomelatine at the 5-HT2C receptor subtype as 5-HT2C receptors that exert an inhibitory influence on mesolimbic and nigro-striatal dopaminergic pathways are constitutively active (Navailles et al., 2006; Aloyo et al., 2009).
Secondly, the neutral antagonist properties of agomelatine are presumably related to its clinical profile with few side effects and no withdrawal syndrome after abrupt discontinuation (Montgomery et al., 2004). Indeed, long-term treatment with a neutral antagonist such as agomelatine does not increase cell surface expression of 5-HT2C receptors (Millan et al., 2011a). Hence, when agomelatine treatment is discontinued, 5-HT will re-access a normal level of 5-HT2C receptors without the negative consequences linked to changes in 5-HT2C receptor density (Chanrion et al., 2008; Aloyo et al., 2009).
The long-term (14 days) administration of agomelatine also enhances the number of spontaneously active neurons and the bursting activity of dopaminergic neurons in the VTA, two effects probably obtained, at least in part, through the activation of melatonin receptors as they are antagonized by S 22153. Further, the firing rate of 5-hydroxytryptaminergic neurons in the DRN is indirectly increased through a DA D2 receptor-dependent mechanism, while the firing activity of noradrenergic neurons in the LC remains at the control level, perhaps because of the enhanced negative feedback exerted by the up-regulated 5-HT neurotransmission (Chenu et al., 2013).
Although a synergistic mechanism involving the combination of MT1 and MT2 melatonin receptor activation and 5-HT2C receptor blockade can explain the molecular, cellular and behavioural actions of agomelatine (Racagni et al., 2011), the precise mechanism underlying this ‘crosstalk’ between the two receptors remains unknown. Experiments evaluating in HEK293T cells the potential existence of heterodimeric complexes of hMT1 and hMT2 receptors with non-edited h5-HT2C(INI) receptors has provided some details about this interplay (Kamal et al., 2010). Co-immunoprecipitation and bioluminescence resonance energy transfer assays demonstrated that 5-HT2C receptors preferentially form heterodimers with MT2 receptors, but also form, with lower propensity, 5-HT2C homomers or heteromers with MT1 receptors. The formation of MT2-5-HT2CINI and MT1-5-HT2CINI heterodimers in HEK293T cells caused alterations in coupling to ß-arrestin and Gq/ PLC. Basal and maximal 5–HT-activated stimulation of PLC via 5-HT2C receptors was increased in the presence of MT2 and, less markedly, of MT1 receptors. Melatonin enhanced PLC activation via a Pertussis toxin-insensitive Gαq in cells co-expressing MT2 and 5-HT2CINI receptors, suggesting heterodimer transactivation (Kamal et al., 2010). If formation of such heteromers were to occur in vivo, this could lead to a synergistic ‘crosstalk’ between these receptors. Hence, these results at the cellular level have potentially important implications for the understanding of how the two pharmacological properties of agomelatine may translate into a synergistic action.
Effects on circadian rhythms
Agomelatine is unique among antidepressants in modulating circadian rhythms. Thus, agomelatine dose-dependently inhibits the firing of cells in the SCN (the endogeneous master clock) in Syrian hamsters (ED50 = 0.91 mg·kg−1, i.p.) (Ying et al., 1996). Chronic agomelatine (given i.p.. or iontophoretically) also does not alter either the sensitivity or the in vitro response of SCN cells, demonstrating that there is no desensitization of melatonin receptors after repeated administration of the drug (Ying et al., 1998).
A useful approach to examine whether or not a pharmacological agent can influence the circadian clock is to determine if its acute administration induces a permanent phase shift of the rhythms driven by the clock under constant environmental conditions. The chronobiotic effect of agomelatine was evaluated using the validated model of free-running conditions. The latter are obtained by putting the animals in total darkness so that circadian rhythms are not synchronized by light, thereby allowing free-running of the endogenous rhythms of the biological clock – the SCN. In animals in which the period of endogenous circadian rhythms is greater (rat, hamster) or shorter (mice) than 24 h, circadian rhythms are delayed or advanced every day respectively. Under these conditions, agomelatine synchronizes the circadian rhythm to 24 h by phase advancing circadian rhythms every day. In the rat, this effect is (i) dose-dependent (ED50 = 5 mg·kg−1 p.o.); and (ii) concentration-dependent, with a correlation between exposure to agomelatine and re-entrainment of circadian rhythms (Martinet et al., 1996).
The entrainment ability of agomelatine is related to a direct stimulating effect of the drug on receptors located in the SCN. Indeed, agomelatine is unable to resynchronize circadian rhythms when the SCN is lesioned. By contrast, pinealectomy has no influence on the resynchronization of circadian rhythms by either agomelatine or melatonin (Redman and Francis, 1998; Pitrosky et al., 1999).
Prolonged s.c. infusion of agomelatine was administered to test the effect of variable duration of exposure to the drug on resynchronization of the circadian rhythm. A pulse effect (1 h infusion) of agomelatine was sufficient for resynchronizing and as effective as an 8 h infusion. Agomelatine was fully effective after 1 or 8 h s.c. infusion while efficiency decreased with a 16 h infusion, which re-entrained less than half of the animals (Pitrosky et al., 1999). That a short time of exposure to agomelatine is sufficient for resynchronizing circadian rhythms under free-running conditions represents an important finding that explains why the compound resynchronizes circadian rhythms in humans despite a short half-life of around 2 h.
After an 8 h phase-advance of the light–dark (L/D) cycle, agomelatine (1 and 3 mg·kg−1) administered s.c. to Long-Evans rats at the beginning of darkness for 14 days induces a phase-advance and a gradual shift of activity to the onset of darkness similar to that induced by melatonin (Redman et al., 1995). Following a 5 h phase-advance of the 12:12 L/D cycle in the same strain, agomelatine (1 mg·kg−1) phase shifts the free-running rhythms and reduces the number of days needed to re-entrain the animals when administered at the time of the post-, and not at the time of the pre-shift dark onset (Redman and Francis, 1998). Interestingly, the resynchronizing activity of agomelatine has been demonstrated not only in nocturnal, but also in diurnal rodents (Van Reeth et al., 1998).
Re-entrainment in rodents is mediated by a phase-advance of circadian rhythms within a specific therapeutic window (between circadian time 9 and 11), and by restoration of the normal circadian rhythm pattern (Van Reeth et al., 1997). The latter property of agomelatine has also been demonstrated in a model of trypanosome-infected rats with fragmented and disrupted rhythms (Grassi-Zucconi et al., 1996).
In the delayed sleep-phase syndrome model, when free-running rats return to conventional 12:12 L/D cycle, in some of them the onset of activity lags behind that of darkness by about 4 h (negative phase angle difference). In these animals, agomelatine (1, 3 mg·kg−1, s.c.) administered chronically at the beginning of darkness advances locomotor activity and abolishes in 9 days the negative phase shift (Armstrong et al., 1993). In addition to an advance of rhythm onset, agomelatine is able to increase the amplitude of circadian rhythms, such as the daily rhythms in melatonin secretion and core temperature (Castanho et al., 2014).
Agomelatine also influences the sleep/wake cycle architecture in control animals, as demonstrated by the enhanced duration of REM and slow wave sleep (SWS) for 3 h after acute oral administration of the drug (10 and 40 mg·kg−1) shortly before the dark phase of the L/D cycle in rats (Descamps et al., 2009). The same modifications are observed during the following night without additional treatment with agomelatine. Moreover, the compound is without effects when given at light onset. This chronobiotic profile of agomelatine is underlined by the lack of alterations in latencies to SWS and REM sleep and the preservation of the spectral components of the electroencephalogram (EEG) (Cajochen et al., 1997; Quera Salva et al., 2007; Descamps et al., 2009). Indeed, melatonin and the melatonin agonist ramelteon exerted different effects on the parameters mentioned earlier and on power band spectra of the EEG, possibly reflecting the absence of antagonistic action at 5-HT2C receptors. Actually, underscoring the importance of 5-HT2C receptor blockade for agomelatine, the 5-HT2C antagonist S 32006 (10 mg·kg−1), administered i.p. at the onset of the dark phase mimicked the increased SWS provoked by agomelatine, yet diminished REM sleep (Descamps et al., 2009).
Chronic treatment of rats with agomelatine (2000 ppm in the diet) corrects the circadian rhythm abnormalities of motor activity and sleep/wake cycle (e.g. reduced duration of SWS, increased duration of REM sleep) induced by prenatal restraint stress, a model of depression; these effects are blocked by the MT1/MT2 receptor antagonist S22153 (Mairesse et al., 2013).
Ageing has been associated with abnormal circadian time keeping, including changes in rhythms amplitude and period, as well as changes in synchronization of those rhythms by the L/D cycle (Turek et al., 2001). Age-related changes in the mammalian circadian system may be associated with a decline in circulating melatonin levels. In old hamsters showing low circulating levels of endogenous melatonin, agomelatine restores the sensitivity of the circadian clock to its synchronizers (Weibel et al., 2000) and accelerates by approximately 25% the resynchronization of their circadian activity rhythm after an abrupt shift in the L/D cycle (Van Reeth et al., 2001). Chronic administration of agomelatine significantly increases the phase-advancing effects of a light pulse, and induces a lengthening of the free-running period of the activity rhythm in those animals (Van Reeth et al., 2001).
The findings mentioned earlier have been confirmed in young, healthy volunteers receiving agomelatine orally in a wide dose range (5–100 mg). Thus, these studies demonstrated persistent phase-advances of circadian rhythms, apparent even the day following agomelatine administration. Agomelatine produced a phase-advance in the circadian changes in temperature and melatonin levels and advanced the timing of the daily decrease in heart rate (Krauchi et al., 1997). The termination of the sleep period and REM sleep propensity were phase-advanced, without effect on other sleep variables (Cajochen et al., 1997). Phase shifting effects have also been reported in healthy elderly men, with advances in the timing of the temperature and cortisol rhythms induced by agomelatine, again with no effect on sleep variables (Leproult et al., 2005). In depressed patients, agomelatine enhances SWS without modifying REM sleep, and advances the time of sleep onset and that of minimal heart rate (Quera Salva et al., 2007). In line with its mode of action, a treatment with agomelatine improved the amplitude of the circadian rest–activity/sleep–wake cycle and also decreased the symptoms of depression and anxiety (Kasper et al., 2010).
Antidepressant effects in animal models
Resynchronization of biological rhythms may be a therapeutically relevant property for an antidepressant agent as depression involves a disruption of normal circadian rhythmicity, including an abnormal phase relationship of various circadian rhythms with the external environment (Kronfeld-Schor and Einat, 2012). With the limits of such a model in mind (multiple behavioural abnormalities, compensatory mechanisms that alter the adult animal's behavioural response) mice missing MT1 receptors exhibit abnormalities including melatonin-mediated phase shift deficits (Dubocovich et al., 2005) and increases in depressive-like behaviour demonstrated in the forced swim test (FST) (Weil et al., 2006). Unlike agomelatine, melatonin is not effective in depressed patients (Dubocovich, 2006; Hickie and Rogers, 2011). Therefore, the fact that agomelatine possesses 5-HT2C receptor antagonist properties must confer a therapeutic advantage compared with a pure melatonergic agent for treating depression.
The antidepressant effect of agomelatine has been illustrated in several well-established rodent models reflecting core clinical features of depression, including the FST (Bourin et al., 2004), learned helplessness (Bertaina-Anglade et al., 2006), chronic mild stress (Papp et al., 2003), bulbectomy (Norman et al., 2012), psychosocial stress (Schmelting et al., 2014), prenatal restraint stress (Morley-Fletcher et al., 2011; Marrocco et al., 2014) and corticosterone-induced depression/anxiety (Rainer et al., 2012). Effects of agomelatine were principally apparent after chronic treatment. Indeed, acute administration of agomelatine has only variable, weak and inconsistent effects in FST procedures in rodents (M.J. Millan, unpubl. obs.).
The antidepressant effects of agomelatine have been also demonstrated in two genetic models of depression. Thus, in transgenic glucocorticoid receptor-impaired (GR-i) mice, GR receptors are down-regulated, thereby making GR-mediated feedback control of hypothalamic–pituitary–adrenal (HPA) axis activity deficient as in depressed patients (Pepin et al., 1992a,b). Accordingly, GR-i mice exhibit numerous behavioural and biological abnormalities that can be suppressed by evening treatment with agomelatine (10 mg·kg−1, i.p. for 21 days). In addition, chronic agomelatine (for 21 days) reverses the behavioural and neuroplastic changes associated with HPA axis alterations in these GR-i mice (Barden et al., 2005; Paizanis et al., 2010).
Another genetic model of depression is based on a selective breeding of Swiss albino CD1 mice with strikingly different responses in the tail suspension test (TST). The lines of mice were named H/Rouen and NH/Rouen for mice displaying helpless (H) and non-helpless (NH) phenotypes in the TST respectively (El Yacoubi et al., 2003). The H/Rouen line shows great stability in terms of immobility scores, anhedonia and altered 5-hydroxytryptaminergic transmission. Chronic administration of agomelatine (10–50 mg·kg−1, i.p. for 3 weeks) significantly reduces immobility of H/Rouen mice in the TST and increases their sucrose preference as compared with vehicle-treated animals (El Yacoubi et al., 2011).
Agomelatine has proven resynchronizing properties in animal models of depression. It is effective in a chronic psychosocial stress model in tree shrew (Tupaia belangeri) (Fuchs, 2005). Animals show profound disturbances in their circadian rhythms when exposed to the social stress procedure. In this model, chronic agomelatine antagonizes the effects of stress on circadian changes in body temperature while melatonin or fluoxetine do not (Schmelting et al., 2014). Agomelatine also accelerates the re-establishment of normal circadian rhythms of temperature and activity in genetically modified GR-i mice (Barden et al., 2005). Chronic administration of agomelatine increases the amplitude of circadian rhythm activity in mice with corticosterone-induced depression/anxiety, an effect that is not observed after the chronic administration of fluoxetine (Rainer et al., 2012). Finally in rats, chronic treatment with agomelatine also corrects the prenatal restraint stress-induced abnormalities in the circadian rhythm of motor activity (Mairesse et al., 2013).
A number of findings obtained in some of the animal models mentioned earlier strongly suggest that the antidepressant-like effect of agomelatine relies on a synergistic action at both melatonin and 5-HT2C receptors (see Table 1). Thus, in the learned helplessness rat model, neither the daily administration of the 5-HT2C receptor antagonist SB242084 (up to 20 mg·kg−1, i.p.) nor melatonin (2, 10 and 50 mg·kg−1 given orally using the same schedule as agomelatine) provide an equivalent reduction in the number of escape failures than agomelatine (Bertaina-Anglade et al., 2006). In this model, the response to agomelatine [given in the evening at a time when its chronobiotic effects are fully expressed (Van Reeth et al., 1997) ] are prevented by pretreatment with the MT1/MT2 receptor antagonist, S 22153 (20 mg·kg−1, i.p.). In the chronic mild stress model, the time of administration of agomelatine [at the beginning of the light period, or in the late evening, just before the start of the dark period] has no influence on its efficacy (Papp et al., 2003). In fact, the neurobiological mechanism underlying the action of agomelatine at the beginning of the light period is not melatonin-like and cannot be reversed by inhibiting the melatonin receptors with S 22153 (20 mg·kg−1 i.p.) (Papp et al., 2003). This morning action of agomelatine is more probably based on the 5-HT2C antagonist properties of the drug (Dekeyne et al., 2008). In the chronic psychosocial stress model in tree shrew, the actions of agomelatine cannot be mimicked by the administration of either melatonin or a 5 HT2C receptor antagonist (Schmelting et al., 2014), which also supports the idea that the antidepressant-like effect of agomelatine in this model of depression probably relies on a synergistic action at both receptors. In bulbectomized rats, the action of agomelatine needs its 5-HT2C antagonist property because the blockade of this receptor subtype by S 32006 (0.16–10 mg·kg−1) dose-dependently attenuated hyperactivity. As the maximal effect of the 5-HT2C antagonist is less marked than that of agomelatine (at 10 and 50 mg·kg−1), a possible synergy with melatonin agonist properties cannot be excluded (Norman et al., 2012).
Table 1.
Antidepressant activity of agomelatine. Potential synergy between melatonergic agonist and 5-HT2C receptor antagonist properties
Model | Agomelatine | Melatonin | 5-HT2C antagonists | Melatonin antagonist# |
---|---|---|---|---|
Despair test(1) | + | − | − | Not tested |
Learned helplessness(2) | + | − | − | Antagonism |
Bulbectomy(3) | + | − | +* | Not tested |
Chronic mild stress(4) | + | + | +* | Antagonism† |
Transgenic model (GR-i mice)(5) | + | + | ? | Not tested |
Psychosocial stress(6) | + | − | +* | Not tested |
Isolated aggressive mice | + | ±* | + | Not tested |
Marble burying test | + | ±* | + | Not tested |
Full spectrum of antidepressant activity | Melatonergic effect not sufficient | 5-HT2C antagonism not sufficient |
+effect; −no effect; #S22153.
(1) (Bourin et al., 2004); (2) (Bertaina-Anglade et al., 2006); (3) (Norman et al., 2012); (4) (Papp et al., 2003); (5) (Barden et al., 2005; Paizanis et al., 2010); (6) (Schmelting et al., 2014).
Less effective than agomelatine.
**High doses (120–160 mg·kg−1).
Agomelatine given in the evening.
Anxiolytic effects in animal models
Agomelatine possesses anxiolytic properties in several animal models in the same dose range as its antidepressant effect (Table 2). Thus, the anxiolytic-like activity of the compound is comparable with that of the benzodiazepine clorazepate in the plus maze test, the social interaction and Vogel tests (Millan et al., 2005). In the elevated plus maze test, when experiments are carried out during the light period of the diurnal cycle, agomelatine (from 40 mg·kg−1, i.p.) dose-dependently increases the percentage of entries into open arms of the plus maze. In the Vogel test, the morning administration of agomelatine elicits a potent effect. The anxiolytic-like activity of agomelatine in the three tests is comparable with that of the selective 5-HT2C receptor antagonist, SB243,213 (Millan et al., 2005), whereas melatonin is ineffective in all these models. The anxiolytic action of agomelatine in the elevated plus maze depends on a synergistic blockade of 5-HT2C receptors and activation of MT1/MT2 receptors. This conclusion is based on the observations that, firstly, the anxiolytic action does not depend on the time of agomelatine administration (i.e. morning vs. evening), and secondly, is inhibited by the MT1/MT2 receptor antagonist S 22153 when the drug is administered in the evening but not in the morning (Papp et al., 2006). The chronic administration of agomelatine (40–50 mg·kg−1, i.p.) for 3 weeks can reverse increased anxiety in models of depression such as prenatal restraint stress (Morley-Fletcher et al., 2011; Marrocco et al., 2014) and corticosterone-treated mice (Rainer et al., 2012).
Table 2.
Anxiolytic activity of agomelatine. Potential synergy between melatonergic agonist and 5-HT2C antagonist properties
Model | Agomelatine | Melatonin | 5-HT2C antagonists | Melatonin antagonist# |
---|---|---|---|---|
Elevated plus maze(1) | + | + | − | Antagonism |
Social defeat(2) | + | + | ? | Not tested |
Geller Seifter conflict | + | − | + | Not tested |
Vogel conflict(3) | + | − | + | No antagonism |
Social interaction(3) | + | − | + | No antagonism |
Predator scent stress (PTSD model)(4) | + | ? | ? | Not tested |
Predator scent stress(5) | + | ? | ? | Not tested |
Fear conditioning(6) | + | − | − | Antagonism |
Full spectrum of anxiolytic activity | Melatonergic effect not sufficient | 5-HT2C antagonism not sufficient |
+effect ; −no effect; #S22153.
(1) (Papp et al., 2006); (2) (Tuma et al., 2005); (3) (Millan et al., 2005); (4) (Koresh et al., 2012); (5) (Conboy et al., 2009); (6) (Diaz-Mataix L et al., 2012).
In the elevated plus maze test, rats receiving agomelatine (50 mg·kg−1, i.p. for three days) displayed significantly less anxiety-like behaviours following the predator scent stress exposure, a model of post-traumatic stress disorder (PTSD) (Koresh et al., 2012). In this model, the anxiolytic-like effect of agomelatine was accompanied by a normalization of the expression of circadian-related genes (Koresh et al., 2012), which again suggests a major role for the resynchronizing action of agomelatine.
Agomelatine also reduces the duration of vocalization by rats re-exposed to an environment associated with an aversive stimulus (conditioned ultrasonic vocalization test) at both low (10–75 mg·kg−1, i.p.) and high doses (100 and 125 mg·kg−1, i.p.), regardless of the time of administration (Papp et al., 2006). The social defeat test allows detection of antidepressant-like effects of chronically administered drugs. However, when animals are confronted to an aggressive dominant congener on a single occasion only, it is usually regarded as a model of acute stress and is useful to detect anxiolytic-like effects of compounds. Under the latter conditions, agomelatine mimics the anxiolytic-like actions of melatonin against acute social defeat in Wistar rats. The effect of agomelatine is abolished by lesions of the SCN (Tuma et al., 2005), which supports a role for both melatonin and 5-HT2C receptors, highly expressed in this brain area. Indeed, 5-HT2C receptors may be recruited for this anxiolytic action since similar effects are obtained in the same paradigms when using experimental conditions of pharmacological or genetic inactivation of 5-HT2C receptors (Millan et al., 2005; Heisler et al., 2007; Dekeyne et al., 2008).
Procognitive effects in animal models
Depressive disorders may affect the ability to think, concentrate, make decisions, formulate ideas, reason and remember. Less clear are the nature and extent of such disturbances, as well as their specificity to affective illness (Marazziti et al., 2010). As a matter of fact, depressive disorders are associated with impairments in different cognitive domains such as executive function, working memory and attention (Baune et al., 2010; Hammar et al., 2010).
Because dopaminergic and noradrenergic mechanisms in the frontal cortex modulate cognitive and attentional performances, mood and motor behaviours, all of which are deeply perturbed in depressive states, it can be reasonably assumed that the stimulant effects of agomelatine on these monoaminergic systems (Millan et al., 2003) contribute not only to its antidepressant action, but also to improved neurocognitive functions, especially memory, attention and problem-solving. The chronobiotic feature of agomelatine could also be relevant in this aspect as a link may exist between circadian disruption and impairments in learning and memory tasks, especially in the area of memory recall (Fekete et al., 1985; Devan et al., 2001; Craig and McDonald, 2008).
Actually, memory-facilitating effects of agomelatine have been demonstrated experimentally, in addition to its antidepressant effects: studies using a radial-arm water maze showed that the chronic administration of agomelatine (10 mg·kg−1, i.p. for 22 days) reversed spatial memory impairment in the predator-stressed rat (Conboy et al., 2009). This promnesiant effect of agomelatine treatment was associated with an increase in hippocampal levels of the neural cell adhesion molecule, known to be involved in memory consolidation (Conboy et al., 2009).
A cognitive-enhancing property of agomelatine has also been demonstrated in the rat two-trial object recognition model (Bertaina-Anglade et al., 2011; Ladurelle et al., 2012). A single i.p. administration of agomelatine at antidepressant doses (2.5, 10 or 40 mg·kg−1), either in the morning or in the evening, enhances performances in this paradigm (Bertaina-Anglade et al., 2011). Positive acute effects on memory performance are also seen upon administering either melatonin at equivalent doses or upon treatment with the 5-HT2C receptor antagonist SB 242,084 (0.63, 2.5 or 10 mg·kg−1). In this paradigm, chronic i.p. administration of agomelatine (40 mg·kg−1·day−1, for 20 days) is likewise active (Ladurelle et al., 2012), indicative of a sustained influence upon cognitive performance. Finally, chronic treatment with agomelatine reversed the disruption of recognition in the prenatal stress model of depression in rats (Marrocco et al., 2014).
Mechanistic issues for the properties of agomelatine
From melatonin and 5–HT2C receptor-based mechanisms …
While it is not surprising that the chronobiotic effects of agomelatine involve the agonist property of the drug at melatonin receptors, the effect of agomelatine in the resynchronization of circadian rhythms could also involve the 5-HT2C receptors. The literature supports a role for 5-hydroxytryptaminergic ascending pathways in the coordination of circadian rhythms to light stimuli. Indeed, the SCN receives a dense 5-hydroxytryptaminergic projection from the midbrain raphe nuclei (van de Kar and Lorens, 1979; Pickard and Rea, 1997) and 5-HT2C receptors have been visualized in it by immunocytochemistry (Moyer and Kennaway, 1999). These observations have prompted the hypothesis that 5-hydroxytryptaminergic innervation of the SCN may serve to modulate the photic response of the SCN circadian oscillator (Pickard and Rea, 1997; Morin, 1999). In vitro studies on SCN firing rate rhythms in rats and in vivo experimentation on wheel running behaviour in hamsters have confirmed this hypothesis. The involvement of 5-HT2C receptors comes from experiments using the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which provokes a transient inhibition of melatonin production in rats (Kennaway and Moyer, 1998; Kennaway et al., 2001). The effect of DOI is counteracted by SB 242,084, therefore suggesting an effect mediated by 5-HT2C receptors. Moreover, 5-HT2C receptors agonists can enhance N-acetyl transferase activity and melatonin synthesis in the rat pineal gland, and these effects are prevented by pretreatment with 5-HT2C receptors antagonists (Steardo et al., 2000). These findings support a role for 5-HT2C receptors in the modulation of circadian messages at the level of the pineal gland.
… to molecular events
The discovery of the molecular clock machinery provides novel mechanistic insights into how rhythm dysfunction could have drastic behavioural consequences. Endogenous rhythm is generated within SCN cells through the positive and negative feedback actions of several circadian locomotor cycles kaput (CLOCK) gene transcription factors. The circadian clock is based on a series of interconnected transcriptional positive–negative feedback loops that are regulated over the course of 24 h in the absence of environmental input and form the basis for the establishment and maintenance of circadian rhythms in individual cells. In mammals, the CLOCK and brain and muscle Arnt-like protein-1 act as major transcriptional activators by forming a heterodimer that promotes transcription of the Period genes (Per1, Per1 and Per3), the cryptochrome genes (Cry1 and Cry2), as well as many other genes by binding to E-box elements in their promoters (Turek, 2007).
There is a link between CLOCK gene functions and mood regulation (Turek, 2007; Bunney and Potkin, 2008; Mendlewicz, 2009). Multiple mood states – and other circadian perturbations – develop with mutation in a single CLOCK gene: mice with a mutation in the CLOCK gene (CLOCKΔ19) display a complete behavioural profile that is very similar to bipolar patients in the manic state (Roybal et al., 2007). Indeed, chronic treatment with lithium restores the majority of their abnormal behaviours to wild-type levels. CLOCK knockdown circumscribed to the VTA is sufficient to lead to less anxiety in the elevated plus maze test and results in a substantial increase in depression-like behaviour, creating, according to the authors, an overall mixed manic state (Mukherjee et al., 2010). Of course, while anxiety-related behaviours can mostly be controlled through CLOCK expression in the VTA, it is likely that other brain regions contribute to the regulation of depression-like behaviour.
Some of the effects of agomelatine, notably those on the circadian clock, are presumably linked to changes in the gene transcriptional/translational feedback loop. Rhythmic expression of CLOCK genes is seen not only in the SCN, but also outside these nuclei, in brain regions such as the dentate gyrus of the hippocampus, the nucleus accumbens and the frontal cortex (Varcoe et al., 2009). In particular, the chronic administration of agomelatine was found to up-regulate Rev-erbα, Rev-erbβ and Prokineticin2 expression in the SCN, and to modify Per1 and Rev-erbα expression in the frontal cortex in a time-dependent manner; however, no changes in the expression of Per1, Per1, CLOCK, Bmal1 and Npas2 genes were noted in the dentate gyrus (Varcoe et al., 2009).
When examining the relationship between PTSD-like behavioural response patterns and CLOCK genes in rats, a significant association was found between the degree of behavioural disruption resulting from predator scent stress exposure, and long-term changes in Per1 and Per2 gene expression in hippocampal subregions, frontal cortex and SCN areas (Koresh et al., 2012). Changes in the rhythmic expression of Per1 and Per2 could affect the functional integrity of cells, and desynchronization among cell populations within the brain may contribute to psychopathology (Wang et al., 2009). When animals are treated with agomelatine (50 mg·kg−1 for 3 days) immediately after stress exposure, a reduction in the percentage of individuals with the most severe PTSD-like behavioural stress response is observed up to 7 days following stress. This effect of agomelatine is accompanied by changes in the expressions of Per1 and Per1 genes that differ between brain regions: agomelatine induces a decrease in Per1 and Per1 mRNA in the hippocampal sub-areas and in the SCN, and an increase in Per1 mRNA levels in the frontal cortex (Koresh et al., 2012).
Cellular and synaptic effects of agomelatine
Effects linked to neurogenesis
There is compelling neurobiological evidence to suggest that mood disorders are characterized by neuron dendrite shrinkage, glial cell loss, and/or impairments in neuroplasticity and cellular resilience (Tang et al., 2012). The recent findings described later indicate that agomelatine exerts some effects on neurogenesis that may participate in its psychotropic actions. The pro-cognitive effects of agomelatine may also be mediated through the up-regulation of neuroplastic mechanisms as the magnitude of the hippocampal shrinkage reported in certain experimental conditions may partly underlie some of the cognitive deficits that accompany major depression.
Antidepressant treatments increase neural plasticity and adult neurogenesis, especially in the hippocampus (Banasr and Duman, 2007). Chronic agomelatine, like other antidepressants, increases cell proliferation, neurogenesis and cell survival in the hippocampus of rats (Table 3). Chronic (3 weeks), but not acute (4 h) or subchronic (1 week) administration of agomelatine (40 mg·kg−1, i.p.) increases cell proliferation and neurogenesis in the ventral dentate gyrus, a region implicated in emotion processing (Banasr et al., 2006; Soumier et al., 2009). Moreover, agomelatine increases cell maturation and survival in the whole hippocampus (Soumier et al., 2009). Some of these effects need a synergistic action at both MT1/MT2 and 5-HT2C receptor subtypes. Thus, 5-HT2C receptor antagonists such as SB243, 213 and S 32006, but not melatonin, can mimic the effects of agomelatine on cell proliferation, while the promoting effect of agomelatine on cell survival is not reproduced by the 5-HT2C receptor antagonists or melatonin alone, but is antagonized by the melatonin antagonist S 22153 (Soumier et al., 2009).
Table 3.
Effects of agomelatine on neuroplasticity. Potential synergy between melatonergic agonist and 5-HT2C antagonist properties
Model | Agomelatine | Melatonin | 5-HT2C antagonists | Melatonin antagonist# |
---|---|---|---|---|
Cell maturation survival(1) | + | − | − | Antagonism |
Growth factors and Cell signalling | ||||
BDNF in the prefrontal cortex (acute)(2) | + | − | − | Antagonism |
BDNF in the hippocampus (chronic)(1) | + | − | − | Not tested |
pAKT-pGSK3β in the hippocampus (chronic)(1) | + | +(3) | − | Not tested |
Early genes | ||||
Arc in the frontal cortex (acute)(4) | + | − | − | Antagonism |
Glutamate release | ||||
Prefrontal/Frontal cortex(5) | + | − | ± | Not tested |
Full spectrum of antidepressant activity | Melatonergic effect not sufficient | 5-HT2C antagonism not sufficient |
+effect; −no effect; #S22153.
(1) (Soumier et al., 2009); (2) (Molteni et al., 2010); (3) (Lee et al., 2006; Tajes et al., 2009); (4) (Racagni et al., 2011); (5) (Tardito et al., 2010).
In a depression-like mouse model in which the response of the HPA axis is blunted by corticosterone treatment via drinking water (David et al., 2009), a 4 week treatment with agomelatine (10 or 40 mg·kg−1 i.p.) can reverse the decrease in hippocampal cell proliferation and increase the maturation of newborn neurons. These neuroplastic effects of agomelatine occur together with an improved depressive/anxiety-like phenotype of the mice, and a normalization of their disturbed circadian rhythms (Rainer et al., 2012).
Agomelatine also reverses the neuroplastic changes and helpless behaviour associated with HPA axis alterations in the transgenic GR-i mouse model (Paizanis et al., 2010). In particular, a 21 day treatment of these mice with agomelatine increases the survival of newly formed cells in the ventral part of the hippocampus without changing their phenotypic differentiation into neurons.
Accordingly, under stress-induced conditions, agomelatine administered for several weeks extends the increased survival of newly formed neurons to the entire dentate gyrus. A 3–6 week treatment with agomelatine (40 mg·kg−1, i.p.) reverses the reduction of neurogenesis induced in the ventral hippocampus of rats after prenatal restraint stress (Morley-Fletcher et al., 2011). In a chronic foot shock stress paradigm, c-Fos expression is reduced in the dentate gyrus, and chronic agomelatine treatment reverses this effect and normalizes neuronal activity to basal levels. Chronic agomelatine also enhances hippocampal cell proliferation in rats concurrently exposed to chronic stress and promotes survival of the newly born cells selectively in the ventral hippocampus (Dagyte et al., 2010). Finally, agomelatine treatment reverses the stress-induced decrease in doublecortin (DCX) expression. Taken together, these data indicate that the benefit of agomelatine's action in situations of stress, and its antidepressant activity, may depend on the ability to reverse stress-affected neuronal activity and promote hippocampal neurogenesis (Dagyte et al., 2010). The effects of agomelatine on hippocampal neurogenesis have also been investigated in the situation of anhedonia in the chronic mild stress paradigm. While chronic mild stress significantly decreases the newborn cell survival and DCX expression in the dentate gyrus, agomelatine normalizes stress-affected cell survival and partly restores DCX expression to non-stress levels (Dagyte et al., 2011). Finally, the suppression of neurogenesis by hippocampus irradiation eliminated the antidepressant effects of agomelatine in the novelty-suppressed feeding paradigm (David et al., 2008).
Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Associations between reduced hippocampal neurogenesis and depressive-like behaviour are mainly based on indirect findings such as responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressed patients or animal models of depressive behaviour (Shirayama et al., 2002; Hoshaw et al., 2005). Substantial support for the neurotrophic hypothesis of depression is brought by the finding that BDNF knocking down circumscribed to the dorsal dentate gyrus can reduce neuronal differentiation (but not proliferation) (Taliaz et al., 2010). Several behavioural impairments are also noted after the knocking down of neurotrophin expression, specifically in the ventral subiculum, notably an anhedonic-like behaviour. Elevation in hippocampal BDNF expression apparently plays key roles in the behavioural effects of various antidepressant treatments (Taliaz et al., 2011). As for many other antidepressants that have demonstrated a positive impact on neurogenesis, a neurotrophic factor is probably involved in the neurogenetic effects of agomelatine. Chronic agomelatine administration increases whole hippocampal mRNA (Calabrese et al., 2011) and protein contents of BDNF (Soumier et al., 2009; Ladurelle et al., 2012). A similar effect has been seen in the transgenic GR-i mouse model (Paizanis et al., 2010) as, together with helpless behaviour associated with HPA axis alterations, chronic agomelatine reverses the down-regulated expression of BDNF mRNA in these animals. Recent experimental data in the GR-i mouse model revealed the antagonism of certain behavioural and neuroplastic effects of agomelatine by inhibitors of trkB (tropomyosin-related kinase) receptors (L. Lanfumey, pers. comm.).
Acute administration of agomelatine increases BDNF mRNA levels in the prefrontal cortex of rats; this effect relies on the synergistic activity of the antidepressant at MT1/MT2 and 5-HT2C receptors, as it cannot be replicated by either melatonin or a 5-HT2C antagonist, when given separately, but is antagonized by the melatonin antagonist S 22153 (Molteni et al., 2010) (Table 3).
The list of molecular players involved in depression's phenotypes has expanded to include genes from diverse aspects of cellular physiology, especially transcription factors, p11, annexins, proteins of the S-100 family, and many others. Of course, a challenge certainly is to determine whether or not the targets themselves may be therapeutically relevant for human depression. Part of the response relies on the demonstration that these newly identified factors are involved in the mechanistic foundation of existing therapeutics. For example, the activity-regulated cytoskeleton-associated protein (Arc) is another mediator of neuroplastic response relevant to the chronic action of various antidepressants (Pei et al., 2003). The expression of this immediate early gene is known to follow significant time-of-day changes in specific brain regions such as the SCN, the frontal cortex and the dentate gyrus (Varcoe et al., 2009). Arc can be involved in the action of agomelatine as chronic administration of the antidepressant up-regulates Arc mRNA expression in whole hippocampus (Calabrese et al., 2011).
The ERK-cAMP-responsive-element-binding protein (CREB) signal system is involved in the molecular pathways of depression as well as in the mechanism of action of some antidepressants (Almeida et al., 2006; Gourley et al., 2008; Qi et al., 2008; Musazzi et al., 2010a; Galeotti and Ghelardini, 2012). Accordingly, in the model of prenatal stress, adult rats have reduced hippocampal levels of phosphorylated CREB (p-CREB), as expected of a depressive phenotype. In this model, p-CREB signalling returns to control level after the chronic administration of agomelatine (40 mg·kg−1), indicating that this pathway is involved in the action of the compound (Morley-Fletcher et al., 2011).
The antidepressant and procognitive actions of agomelatine are accompanied by modulation of the kinase microtubule-associated protein 2, as well as cytoskeletal microtubule dynamics and synaptic markers such as synaptophysin, postsynaptic density-95 (PSD-95), spinophilin and BDNF in the hippocampus, amygdala and PFC in a region-specific pattern (Ladurelle et al., 2012). In particular, the expression of the dendrite-specific MAP-2 and its phosphorylation at Ser136 were both increased by chronic agomelatine in the hippocampus and at a much higher level in the amygdala. These findings, which may be related to regulation of microtubule dynamics and/or dendritic remodelling, as also seen with fluoxetine (Bessa et al., 2009), are in agreement with the findings that (sub)chronic administration of different classes of antidepressants (imipramine, desipramine, fluvoxamine) can affect MAP-2 expression and/or phosphorylation in rat brain regions (Perez et al., 1995; Miyamoto et al., 1997; Iwata et al., 2006). The NMDA receptor antagonist ketamine, endowed with a rapid antidepressant action (Machado-Vieira et al., 2009), similarly increased PSD-95 and synapsin I expressions, resulting in synaptic strengthening (Li et al., 2010; Li and Jope, 2010).
Chronic agomelatine administration to rats potentiates the phosphorylation of the β isoform of glycogen synthase kinase-3 (GSK3β) in the total hippocampus (Soumier et al., 2009) (Table 3). GSK3β exerts profound influences on cellular architecture and plasticity. GSK3β can be inhibited by phosphorylation through several kinases, and an impairment of this inhibitory control can result in abnormally high GSK3β activity, a condition that can have detrimental effects on neuronal plasticity, structure and survival (Jope and Roh, 2006). GSK-3β can be phosphorylated by ERK1/2 and agomelatine does activate these kinases that are implicated in cell survival mechanisms (Soumier et al., 2009). GSK3β has received much attention because the mood stabilizer lithium is a direct inhibitor of this enzyme, a finding that raised the possibility that GSK3β may not be adequately controlled in mood disorders (Jope and Roh, 2006; Li and Jope, 2010). GSK3β could represent another potential connection between circadian rhythms and treatment of mood disorders as it is one of several kinases involved in the regulation of circadian cycles through the phosphorylation of Per and other circadian gene products (Takahashi, 2004). Clearly, it is important to clarify further the possible link between the action of agomelatine and the expression of this kinase because a dys-regulated GSK3β pathway may also have multiple effects that could impair neural plasticity, such as modulation of neuronal architecture, neurogenesis, gene expression and the resilience of neurons to stress, all of which have also been associated with the mechanism of action of the compound. BDNF also plays a role in the modulation of circadian rhythms and fluctuations of the expression of this neurotrophic factor and its receptor occur over the course of a circadian cycle (Cirulli and Alleva, 2009). Besides, it has been hypothesized that GSK3β may be a central regulator of the endogenous circadian clock. The link between the chronobiotic actions of agomelatine and the mediators of neuroplastic responses and signalling pathways mentioned earlier therefore supports the hypothesized mode of action of the compound (Racagni et al., 2011).
Involvement of the glutamate pathway
The impact of agomelatine on glutamate signalling has been examined as this excitatory amino acid neurotransmitter and its receptors play a role in depression and antidepressant activity (Mitchell and Baker, 2010). Drugs with glutamate-based mechanisms are endowed with accelerated onset of activity. Currently, the non-competitive NMDA receptor antagonist ketamine appears an attractive therapeutic agent for treatment-resistant patients with depressive disorder (Machado-Vieira et al., 2009). However, the cognitive and dissociative side effects of ketamine limit its widespread application. The exact implication of glutamate in depression and antidepressant treatment is far from clear because of the many interactions with other neurotransmitter systems, for example through kinase phosphorylation and BDNF synthesis in the case of ketamine (Autry et al., 2011). A number of other drugs [e.g. selective GluN2B receptor (NR2B) antagonists, positive modulators of AMPA receptors, and metabotropic glutamate (mGlu) receptor agonists/antagonists for nomenclature see Alexander et al., 2013a] also exhibit antidepressant-like effects in animal models of depression (Hashimoto, 2011), but no clinical studies demonstrating the effectiveness of these drugs are available.
Through a synergistic interaction between its MT1/MT2 and 5-HT2C receptor components, agomelatine modulates glutamate signalling, engaging time-dependent modifications of receptors and transporters in circumscribed regions involved in the regulation of mood, circadian rhythms and cognition (Racagni et al., 2011). Thus, the acute administration of agomelatine (40 mg·kg−1 i.p.) abolishes the restraint stress-induced increase in extracellular glutamate efflux in limbic structures such as the basolateral and central nuclei of the amygdala and the hippocampus (Reagan et al., 2012). As previously found with other antidepressants (Bonanno et al., 2005), chronic administration of agomelatine (40 mg·kg−1, i.p., for 21 days) significantly reduced endogenous release of glutamate from hippocampal synaptosomes and decreased the accumulation of SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) complex, a key molecular effector of vesicle docking, priming and fusion at presynaptic membranes (Milanese et al., 2013). Long-term administration of antidepressants elicits adaptive changes in the functional status of mGlu receptors (Paul and Skolnick, 2003; Palucha and Pilc, 2007). This is also the case of chronic agomelatine, which normalizes glutamate release and the expression of mGlu2/3 and mGlu5 receptor mRNAs in the hippocampus of rats subjected to prenatal restraint stress (Morley-Fletcher et al., 2011; Marrocco et al., 2014). Further, chronic agomelatine treatment modulates the expression of mGlu receptor mRNA in a time- and region-dependent manner (Varcoe et al., 2009). For example, agomelatine increases the evening expression of mGlu1, mGlu4, mGlu6 and mGlu8 receptors in the frontal cortex, while some transcripts can be over-expressed in the morning (mGlu7) and at night (mGlu8). Other time-dependent changes are induced by agomelatine, for example in the SCN (where mGlu7 receptor levels increased at night and decreased during subjective day). Those changes in the timing of glutamate receptors could be conveyed by rhythmicity of certain CLOCK gene's transcription factors (Varcoe et al., 2009).
The mGlu receptor subtypes cited earlier are negatively coupled to AC, are expressed by both neuronal and glial cells, and are predominantly localized to axon terminals. Thus, any increased expression of these receptors may be associated with the fact that chronic agomelatine also reduces glutamate release in the prefrontal/frontal cortex of rats exposed to acute footshock stress (Musazzi et al., 2010b; Tardito et al., 2010). The latter effect of agomelatine on glutamate signalling is again coupled to its synergistic action on melatonergic and 5-hydroxytryptaminergic pathways since it is only partly replicated by 5-HT2C receptor blockade with S 32006, and cannot be obtained after melatonin treatment (Tardito et al., 2010) (Table 3).
The vesicular glutamate transporters (vGLUTs; Alexander et al., 2013b) are involved in the loading of glutamate into synaptic vesicles. A reduced expression of these transporters has been linked to depressive behaviour in both clinical and preclinical studies. Specifically, there is evidence that the expression of the vGLUT type 1 (vGLUT1) is reduced in an animal model of depression (Zink et al., 2010), and knocking down vGLUT1 expression provokes depressive-like behaviours in mice (Tordera et al., 2007). In addition, reduced expression of vGLUT1 and vGLUT2 has been observed in post mortem brains of depressed subjects (Uezato et al., 2009). The expression of vGLUT1 mRNA is up-regulated in the frontal cortex following chronic agomelatine treatment (Varcoe et al., 2009). Similar effects have been reported with other antidepressant classes in rodents (Moutsimilli et al., 2005; Tordera et al., 2005). In addition, chronic agomelatine treatment modified the pattern of expression of vGLUT2 mRNA in the SCN and frontal cortex, with an increased expression during the night, and a decrease during the subjective day (Varcoe et al., 2009).
Finally, pro-cognitive effects of agomelatine may be mediated through glutamatergic processes involved in the induction of long-term potentiation and in memory formation, possibly by normalizing stress-induced alterations in the glutamatergic system (Musazzi et al., 2010b; Tardito et al., 2010).
Effects on inflammatory markers
Specific components of the immune/inflammatory system play a crucial role in the antidepressant response and thereby in depression aetiopathology. Chronic treatment with agomelatine significantly reduced the LPS-induced up-regulation of the pro-inflammatory cytokines IL-1β and IL-6 in the rat brain as well as at peripheral level (Molteni et al., 2013). Agomelatine also altered the expression of enzymes related to the kynurenine pathway thought to represent important mediators in inflammation-related depression. Thus, agomelatine appears to interfere with molecular systems involved with inflammatory responses.
Conclusion
Agomelatine exerts psychotropic effects upon mood and anxious states. The psychotropic actions of agomelatine in a range of experimental models are based on a synergistic interplay of its melatonergic agonist and 5-HT2C receptor neutral antagonist actions (Racagni et al., 2011). If confirmed in vivo, the demonstration of a ‘crosstalk’ between these different receptors would represent a major step forward in the understanding of this synergistic action (Kamal et al., 2010). Our knowledge concerning the mechanisms of action and functional properties of agomelatine is being progressively enhanced. Agomelatine affects a number of neurobiological events including transcriptional-translational molecular circadian clock, neurogenesis, synaptic remodelling and glutamate signalling. It will be important to further characterize these properties, and to explore other possible mechanisms of action in order to deepen our understanding of the neurobiological substrates underpinning the distinctive functional and therapeutic profile of agomelatine.
Glossary
- Arc
activity-regulated cytoskeleton-associated protein
- BDNF
brain-derived neurotrophic factor
- CLOCK
circadian locomotor cycles kaput
- CREB
cAMP-responsive element binding protein
- DA
dopamine
- DCX
doublecortin
- DOI
1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
- DRN
dorsal raphé nuclei
- DSPS
delayed sleep-phase syndrome
- FST
forced swim test
- GR-i
glucocorticoid receptor impaired
- GSK
glycogen synthase kinase
- H
helpless
- HPA
hypothalamic pituitary adrenal
- LC
locus coeruleus
- L/D
light-dark
- mGlu
metabotropic glutamate
- MT
melatonin
- NA
noradrenaline
- NH
non-helpless
- PTSD
post-traumatic stress disorder
- REM
rapid eye movement
- SCN
suprachiasmatic nucleus
- SWS
slow wave sleep
- TST
tail suspension test
- vGLUT
vesicular glutamate transporters
- VTA
ventral tegmental area
Conflict of interest
All authors are full-time employees of Servier and have no other interests to declare.
References
- Adam G, Guardiola-Lemaitre B, Yous S, Lesieur D, Morgan P, Howell HE, et al. [New naphthalenic ligands of melatoninergic receptors] J Pharm Belg. 1992;47:374–380. [PubMed] [Google Scholar]
- Aira Z, Buesa I, Salgueiro M, Bilbao J, Aguilera L, Zimmermann M, et al. Subtype-specific changes in 5-HT receptor-mediated modulation of C fibre-evoked spinal field potentials are triggered by peripheral nerve injury. Neuroscience. 2010;168:831–841. doi: 10.1016/j.neuroscience.2010.04.032. [DOI] [PubMed] [Google Scholar]
- Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ CGTP Collaborators. The Concise Guide to PHARMACOLOGY 2013/14: G protein-coupled receptors. Br J Pharmacol. 2013a;170:1459–1581. doi: 10.1111/bph.12445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ CGTP Collaborators. The Concise Guide to PHARMACOLOGY 2013/14: Transporters. Br J Pharmacol. 2013b;170:1706–1796. doi: 10.1111/bph.12450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Almeida RC, Souza DG, Soletti RC, Lopez MG, Rodrigues AL, Gabilan NH. Involvement of PKA, MAPK/ERK and CaMKII, but not PKC in the acute antidepressant-like effect of memantine in mice. Neurosci Lett. 2006;395:93–97. doi: 10.1016/j.neulet.2005.10.057. [DOI] [PubMed] [Google Scholar]
- Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol Ther. 2009;121:160–173. doi: 10.1016/j.pharmthera.2008.10.010. [DOI] [PubMed] [Google Scholar]
- Armstrong SM, McNulty OM, Guardiola-Lemaitre B, Redman JR. Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS) Pharmacol Biochem Behav. 1993;46:45–49. doi: 10.1016/0091-3057(93)90315-k. [DOI] [PubMed] [Google Scholar]
- Audinot V, Mailliet F, Lahaye BC, Bonnaud A, Le Gall A, Amosse C, et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003;16:553–561. doi: 10.1007/s00210-003-0751-2. [DOI] [PubMed] [Google Scholar]
- Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95. doi: 10.1038/nature10130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Banasr M, Duman RS. Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets. 2007;6:311–320. doi: 10.2174/187152707783220929. [DOI] [PubMed] [Google Scholar]
- Banasr M, Soumier A, Hery M, Mocaer E, Daszuta A. Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psychiatry. 2006;59:1087–1096. doi: 10.1016/j.biopsych.2005.11.025. [DOI] [PubMed] [Google Scholar]
- Barden N, Shink E, Labbe M, Vacher R, Rochford J, Mocaer E. Antidepressant action of agomelatine (S 20098) in a transgenic mouse model. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:908–916. doi: 10.1016/j.pnpbp.2005.04.032. [DOI] [PubMed] [Google Scholar]
- Baune BT, Miller R, McAfoose J, Johnson M, Quirk F, Mitchell D. The role of cognitive impairment in general functioning in major depression. Psychiatry Res. 2010;176:183–189. doi: 10.1016/j.psychres.2008.12.001. [DOI] [PubMed] [Google Scholar]
- Bertaina-Anglade V, la Rochelle CD, Boyer PA, Mocaer E. Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model. Behav Pharmacol. 2006;17:703–713. doi: 10.1097/FBP.0b013e3280116e5c. [DOI] [PubMed] [Google Scholar]
- Bertaina-Anglade V, Drieu-La-Rochelle C, Mocaer E, Seguin L. Memory facilitating effects of agomelatine in the novel object recognition memory paradigm in the rat. Pharmacol Biochem Behav. 2011;98:511–517. doi: 10.1016/j.pbb.2011.02.015. [DOI] [PubMed] [Google Scholar]
- Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009;14:764–773. doi: 10.1038/mp.2008.119. 739. [DOI] [PubMed] [Google Scholar]
- de Bodinat C, Guardiola-Lemaitre B, Mocaer E, Renard P, Munoz C, Millan MJ. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov. 2010;9:628–642. doi: 10.1038/nrd3140. [DOI] [PubMed] [Google Scholar]
- Bonanno G, Giambelli R, Raiteri L, Tiraboschi E, Zappettini S, Musazzi L, et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci. 2005;25:3270–3279. doi: 10.1523/JNEUROSCI.5033-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bonnefond C, Martinet L, Lesieur D, Adam G, Guardiola-Lemaitre B. Characterization of S-20098, a new melatonin analog. In: Touitou Y, Arendt J, Pevet P, editors. Melatonin and the Pineal Gland. From Basic Science to Clinical Application. Amsterdam: Elsevier; 1993. pp. 123–126. [Google Scholar]
- Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J Psychiatry Neurosci. 2004;29:126–133. [PMC free article] [PubMed] [Google Scholar]
- Brea J, Castro-Palomino J, Yeste S, Cubero E, Parraga A, Dominguez E, et al. Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors. Curr Top Med Chem. 2010;10:493–503. doi: 10.2174/156802610791111524. [DOI] [PubMed] [Google Scholar]
- Bunney JN, Potkin SG. Circadian abnormalities, molecular clock genes and chronobiological treatments in depression. Br Med Bull. 2008;86:23–32. doi: 10.1093/bmb/ldn019. [DOI] [PubMed] [Google Scholar]
- Cajochen C, Krauchi K, Mori D, Graw P, Wirz-Justice A. Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis. Am J Physiol. 1997;272:R1189–R1196. doi: 10.1152/ajpregu.1997.272.4.R1189. [DOI] [PubMed] [Google Scholar]
- Calabrese F, Molteni R, Gabriel C, Mocaer E, Racagni G, Riva MA. Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine. Psychopharmacology (Berl) 2011;215:267–275. doi: 10.1007/s00213-010-2129-8. [DOI] [PubMed] [Google Scholar]
- Castanho A, Bothorel B, Seguin L, Mocaer E, Pevet P. Like melatonin, agomelatine (S20098) increases the amplitude of oscillations of two clock outputs: melatonin and temperature rhythms. Chronobiol Int. 2014;31:371–381. doi: 10.3109/07420528.2013.860457. [DOI] [PubMed] [Google Scholar]
- Cervantes-Duran C, Vidal-Cantu GC, Barragan-Iglesias P, Pineda-Farias JB, Bravo-Hernandez M, Murbartian J, et al. Role of peripheral and spinal 5-HT2B receptors in formalin-induced nociception. Pharmacol Biochem Behav. 2012;102:30–35. doi: 10.1016/j.pbb.2012.03.015. [DOI] [PubMed] [Google Scholar]
- Chagraoui A, Protais P, Filloux T, Mocaer E. Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats. Psychopharmacology (Berl) 2003;170:17–22. doi: 10.1007/s00213-003-1465-3. [DOI] [PubMed] [Google Scholar]
- Chanrion B, Mannoury LC, Gavarini S, Seimandi M, Vincent L, Pujol JF, et al. Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol. 2008;73:748–757. doi: 10.1124/mol.107.041574. [DOI] [PubMed] [Google Scholar]
- Chenu F, El MM, Blier P. Electrophysiological effects of repeated administration of agomelatine on the dopamine, norepinephrine, and serotonin systems in the rat brain. Neuropsychopharmacology. 2013;38:275–284. doi: 10.1038/npp.2012.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cirulli F, Alleva E. The NGF saga: from animal models of psychosocial stress to stress-related psychopathology. Front Neuroendocrinol. 2009;30:379–395. doi: 10.1016/j.yfrne.2009.05.002. [DOI] [PubMed] [Google Scholar]
- Conboy L, Tanrikut C, Zoladz PR, Campbell AM, Park CR, Gabriel C, et al. 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. Int J Neuropsychopharmacol. 2009;12:329–341. doi: 10.1017/S1461145708009255. [DOI] [PubMed] [Google Scholar]
- Craig LA, McDonald RJ. Chronic disruption of circadian rhythms impairs hippocampal memory in the rat. Brain Res Bull. 2008;76:141–151. doi: 10.1016/j.brainresbull.2008.02.013. [DOI] [PubMed] [Google Scholar]
- Dagyte G, Trentani A, Postema F, Luiten PG, Den Boer JA, Gabriel C, et al. The novel antidepressant agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in chronically stressed rats. CNS Neurosci Ther. 2010;16:195–207. doi: 10.1111/j.1755-5949.2009.00125.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dagyte G, Crescente I, Postema F, Seguin L, Gabriel C, Mocaer E, et al. Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav Brain Res. 2011;218:121–128. doi: 10.1016/j.bbr.2010.11.045. [DOI] [PubMed] [Google Scholar]
- David DJ, Gabriel-Gracia C, Mocaer E, Tanaka K, Gardier AM, Hen R. 2008. [Hippocampal neurogenesis may be required for behavioral effects of Agomelatine in the novelty suppressed feeding test e]. Program No. 160.10/EE23 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online.
- David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–493. doi: 10.1016/j.neuron.2009.04.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dekeyne A, Mannoury LC, Gobert A, Brocco M, Lejeune F, Serres F, et al. S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology (Berl) 2008;199:549–568. doi: 10.1007/s00213-008-1177-9. [DOI] [PubMed] [Google Scholar]
- Delagrange P, Guardiola-Lemaitre B. Melatonin, its receptors, and relationships with biological rhythm disorders. Clin Neuropharmacol. 1997;20:482–510. doi: 10.1097/00002826-199712000-00002. [DOI] [PubMed] [Google Scholar]
- Descamps A, Rousset C, Millan MJ, Spedding M, Delagrange P, Cespuglio R. Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep–wake cycle architecture. Psychopharmacology (Berl) 2009;205:93–106. doi: 10.1007/s00213-009-1519-2. [DOI] [PubMed] [Google Scholar]
- Devan BD, Goad EH, Petri HL, Antoniadis EA, Hong NS, Ko CH, et al. Circadian phase-shifted rats show normal acquisition but impaired long-term retention of place information in the water task. Neurobiol Learn Mem. 2001;75:51–62. doi: 10.1006/nlme.1999.3957. [DOI] [PubMed] [Google Scholar]
- Diaz-Mataix L, Mocaer E, Seguin L, LeDoux JE. The antidepressant agomelatine reduces fear long term memory but not acquisition or short term expression of fear memories. Involvement of the melatonergic agonist and 5HT2C antagonist properties. Eur Neuropsychopharmacol. 2012;22:S270. [Google Scholar]
- Dubocovich ML. Agomelatine targets a range of major depressive disorder symptoms. Curr Opin Investig Drugs. 2006;7:670–680. [PubMed] [Google Scholar]
- Dubocovich ML, Hudson RL, Sumaya IC, Masana MI, Manna E. Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in the C57BL/6 mouse. J Pineal Res. 2005;39:113–120. doi: 10.1111/j.1600-079X.2005.00230.x. [DOI] [PubMed] [Google Scholar]
- El Yacoubi M, Bouali S, Popa D, Naudon L, Leroux-Nicollet I, Hamon M, et al. Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression. Proc Natl Acad Sci U S A. 2003;100:6227–6232. doi: 10.1073/pnas.1034823100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- El Yacoubi M, Dubois M, Gabriel C, Mocaer E, Vaugeois JM. Chronic agomelatine and fluoxetine induce antidepressant-like effects in H/Rouen mice, a genetic mouse model of depression. Pharmacol Biochem Behav. 2011;100:284–288. doi: 10.1016/j.pbb.2011.08.001. [DOI] [PubMed] [Google Scholar]
- Fekete M, van Ree JM, Niesink RJ, de Wied D. Disrupting circadian rhythms in rats induces retrograde amnesia. Physiol Behav. 1985;34:883–887. doi: 10.1016/0031-9384(85)90008-3. [DOI] [PubMed] [Google Scholar]
- Fuchs E. Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder. CNS Spectr. 2005;10:182–190. doi: 10.1017/s1092852900010038. [DOI] [PubMed] [Google Scholar]
- Galeotti N, Ghelardini C. Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol. 2012;15:781–793. doi: 10.1017/S1461145711000897. [DOI] [PubMed] [Google Scholar]
- Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. Hum Psychopharmacol. 2008;23:571–585. doi: 10.1002/hup.964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, et al. Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry. 2008;63:353–359. doi: 10.1016/j.biopsych.2007.07.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grassi-Zucconi G, Semprevivo M, Mocaer E, Kristensson K, Bentivoglio M. Melatonin and its new agonist S-20098 restore synchronized sleep fragmented by experimental trypanosome infection in the rat. Brain Res Bull. 1996;39:63–68. doi: 10.1016/0361-9230(95)02032-2. [DOI] [PubMed] [Google Scholar]
- Guardiola-Lemaitre B, Quera-Salva MA. Melatonin and regulation of sleep and circadian disorders. In: Krygeer MH, Roth T, Dement WC, editors. Principles and Practice of Sleep medicine. Elsevier edn. Philadelphia: Elsevier-Saunders; 2011. pp. 420–430. [Google Scholar]
- Hammar A, Sorensen L, Ardal G, Oedegaard KJ, Kroken R, Roness A, et al. Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm. Scand J Psychol. 2010;51:304–308. doi: 10.1111/j.1467-9450.2009.00765.x. [DOI] [PubMed] [Google Scholar]
- Hanoun N, Mocaer E, Boyer PA, Hamon M, Lanfumey L. Differential effects of the novel antidepressant agomelatine (S 20098) versus fluoxetine on 5-HT1A receptors in the rat brain. Neuropharmacology. 2004;47:515–526. doi: 10.1016/j.neuropharm.2004.06.003. [DOI] [PubMed] [Google Scholar]
- Hashimoto K. The role of glutamate on the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1558–1568. doi: 10.1016/j.pnpbp.2010.06.013. [DOI] [PubMed] [Google Scholar]
- Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH. Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav. 2007;6:491–496. doi: 10.1111/j.1601-183X.2007.00316.x. [DOI] [PubMed] [Google Scholar]
- Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet. 2011;378:621–631. doi: 10.1016/S0140-6736(11)60095-0. [DOI] [PubMed] [Google Scholar]
- Hoshaw BA, Malberg JE, Lucki I. Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res. 2005;1037:204–208. doi: 10.1016/j.brainres.2005.01.007. [DOI] [PubMed] [Google Scholar]
- Iwata M, Shirayama Y, Ishida H, Kawahara R. Hippocampal synapsin I, growth-associated protein-43, and microtubule-associated protein-2 immunoreactivity in learned helplessness rats and antidepressant-treated rats. Neuroscience. 2006;141:1301–1313. doi: 10.1016/j.neuroscience.2006.04.060. [DOI] [PubMed] [Google Scholar]
- Jaffre F, Callebert J, Sarre A, Etienne N, Nebigil CG, Launay JM, et al. Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts. Circulation. 2004;110:969–974. doi: 10.1161/01.CIR.0000139856.20505.57. [DOI] [PubMed] [Google Scholar]
- Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets. 2006;7:1421–1434. doi: 10.2174/1389450110607011421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kamal M, Guillaume JL, Daulat A, Chen P, Mannoury la Cour C, Millan M, et al. Evidence for functional heteromerization of melatonin MT1 and MT2 receptors with serotonin (5-HT)2C receptors. Int J Neuropsychopharmacol. 2010;13:P3–P23. [Google Scholar]
- van de Kar LD, Lorens SA. Differential serotonergic innervation of individual hypothalamic nuclei and other forebrain regions by the dorsal and median midbrain raphe nuclei. Brain Res. 1979;162:45–54. doi: 10.1016/0006-8993(79)90754-6. [DOI] [PubMed] [Google Scholar]
- Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, Smeraldi E, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71:109–120. doi: 10.4088/JCP.09m05347blu. [DOI] [PubMed] [Google Scholar]
- Kennaway DJ, Moyer RW. Serotonin 5-HT2c agonists mimic the effect of light pulses on circadian rhythms. Brain Res. 1998;806:257–270. doi: 10.1016/s0006-8993(98)00746-x. [DOI] [PubMed] [Google Scholar]
- Kennaway DJ, Moyer RW, Voultsios A, Varcoe TJ. Serotonin, excitatory amino acids and the photic control of melatonin rhythms and SCN c-FOS in the rat. Brain Res. 2001;897:36–43. doi: 10.1016/s0006-8993(01)02091-1. [DOI] [PubMed] [Google Scholar]
- Kennedy SH, Rizvi SJ. Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness. CNS Drugs. 2010;24:479–499. doi: 10.2165/11534420-000000000-00000. [DOI] [PubMed] [Google Scholar]
- Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol. 2008;28:329–333. doi: 10.1097/JCP.0b013e318172b48c. [DOI] [PubMed] [Google Scholar]
- Koresh O, Kozlovsky N, Kaplan Z, Zohar J, Matar MA, Cohen H. The long-term abnormalities in circadian expression of Period 1 and Period 2 genes in response to stress is normalized by agomelatine administered immediately after exposure. Eur Neuropsychopharmacol. 2012;22:205–221. doi: 10.1016/j.euroneuro.2011.07.012. [DOI] [PubMed] [Google Scholar]
- Krauchi K, Cajochen C, Mori D, Graw P, Wirz-Justice A. Early evening melatonin and S-20098 advance circadian phase and nocturnal regulation of core body temperature. Am J Physiol. 1997;272:R1178–R1188. doi: 10.1152/ajpregu.1997.272.4.R1178. [DOI] [PubMed] [Google Scholar]
- Kronfeld-Schor N, Einat H. Circadian rhythms and depression: human psychopathology and animal models. Neuropharmacology. 2012;62:101–114. doi: 10.1016/j.neuropharm.2011.08.020. [DOI] [PubMed] [Google Scholar]
- Ladurelle N, Gabriel C, Viggiano A, Mocaer E, Baulieu EE. Agomelatine (S20098) modulates the expression of cytoskeletal microtubular proteins, synaptic markers and BDNF in the rat hippocampus, amygdala and PFC. Psychopharmacology (Berl) 2012;221:493–509. doi: 10.1007/s00213-011-2597-5. [DOI] [PubMed] [Google Scholar]
- Lee SH, Chun W, Kong PJ, Han JA, Cho BP, Kwon OY, et al. Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus. J Pineal Res. 2006;40:79–85. doi: 10.1111/j.1600-079X.2005.00283.x. [DOI] [PubMed] [Google Scholar]
- Leproult R, Van Onderbergen A, L'hermite-Baleriaux M, Van Cauter E, Copinschi G. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 2005;63:298–304. doi: 10.1111/j.1365-2265.2005.02341.x. [DOI] [PubMed] [Google Scholar]
- Li JZ, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP, et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci U S A. 2013;110:9950–9955. doi: 10.1073/pnas.1305814110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964. doi: 10.1126/science.1190287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li X, Jope RS. Is glycogen synthase kinase-3 a central modulator in mood regulation? Neuropsychopharmacology. 2010;35:2143–2154. doi: 10.1038/npp.2010.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin SY, Chang WJ, Lin CS, Huang CY, Wang HF, Sun WH. Serotonin receptor 5-HT2B mediates serotonin-induced mechanical hyperalgesia. J Neurosci. 2011;31:1410–1418. doi: 10.1523/JNEUROSCI.4682-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Linnik IV, McKie S, Stark JA, Luckman S, Seguin L, Mocaer E, et al. The novel antidepressant, agomelatine, blocks cerebral 5-HT2C receptors in vivo: a phMRI challenge study in rats. Eur Neuropsychopharmacol. 2009;19:S259. [Google Scholar]
- Machado-Vieira R, Salvadore G, Diazgranados N, Zarate CA., Jr Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther. 2009;123:143–150. doi: 10.1016/j.pharmthera.2009.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mairesse J, Silletti V, Laloux C, Zuena AR, Giovine A, Consolazione M, et al. Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. Int J Neuropsychopharmacol. 2013;16:323–338. doi: 10.1017/S1461145711001970. [DOI] [PubMed] [Google Scholar]
- Marazziti D, Consoli G, Picchetti M, Carlini M, Faravelli L. Cognitive impairment in major depression. Eur J Pharmacol. 2010;626:83–86. doi: 10.1016/j.ejphar.2009.08.046. [DOI] [PubMed] [Google Scholar]
- Marrocco J, Reynaert ML, Gatta E, Gabriel C, Mocaer E, Di PS, et al. The effects of antidepressant treatment in prenatally stressed rats support the glutamatergic hypothesis of stress-related disorders. J Neurosci. 2014;34:2015–2024. doi: 10.1523/JNEUROSCI.4131-13.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martinet L, Guardiola-Lemaitre B, Mocaer E. Entrainment of circadian rhythms by S-20098, a melatonin agonist, is dose and plasma concentration dependent. Pharmacol Biochem Behav. 1996;54:713–718. doi: 10.1016/0091-3057(95)02221-x. [DOI] [PubMed] [Google Scholar]
- Martinotti G, Sepede G, Gambi F, Di IG, De BD, Di NM, et al. Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study. J Clin Psychopharmacol. 2012;32:487–491. doi: 10.1097/JCP.0b013e31825d6c25. [DOI] [PubMed] [Google Scholar]
- McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther. 2007;114:222–232. doi: 10.1016/j.pharmthera.2007.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mendlewicz J. Disruption of the circadian timing systems: molecular mechanisms in mood disorders. CNS Drugs. 2009;23(Suppl. 2):15–26. doi: 10.2165/11318630-000000000-00000. [DOI] [PubMed] [Google Scholar]
- Milanese M, Tardito D, Musazzi L, Treccani G, Mallei A, Bonifacino T, et al. Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes. BMC Neurosci. 2013;14:75. doi: 10.1186/1471-2202-14-75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, et al. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther. 2003;306:954–964. doi: 10.1124/jpet.103.051797. [DOI] [PubMed] [Google Scholar]
- Millan MJ, Brocco M, Gobert A, Dekeyne A. Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl) 2005;177:448–458. doi: 10.1007/s00213-004-1962-z. [DOI] [PubMed] [Google Scholar]
- Millan MJ, Marin P, Kamal M, Jockers R, Chanrion B, Labasque M, et al. The melatonergic agonist and clinically active antidepressant, agomelatine, is a neutral antagonist at 5-HT(2C) receptors. Int J Neuropsychopharmacol. 2011a;14:768–783. doi: 10.1017/S1461145710001045. [DOI] [PubMed] [Google Scholar]
- Millan MJ, Marin P, Kamal M, Jockers R, Chanrion B, Labasque M, et al. The melatonergic agonist and clinically active antidepressant, agomelatine, is a neutral antagonist at 5-HT2C receptors. Int J Neuropsychopharmacol. 2011b;14:768–783. doi: 10.1017/S1461145710001045. [DOI] [PubMed] [Google Scholar]
- Mitchell ND, Baker GB. An update on the role of glutamate in the pathophysiology of depression. Acta Psychiatr Scand. 2010;122:192–210. doi: 10.1111/j.1600-0447.2009.01529.x. [DOI] [PubMed] [Google Scholar]
- Miyamoto S, Asakura M, Sasuga Y, Osada K, Bodaiji N, Imafuku J, et al. Effects of long-term treatment with desipramine on microtubule proteins in rat cerebral cortex. Eur J Pharmacol. 1997;333:279–287. doi: 10.1016/s0014-2999(97)01140-0. [DOI] [PubMed] [Google Scholar]
- Molteni R, Calabrese F, Pisoni S, Gabriel C, Mocaer E, Racagni G, et al. Synergistic mechanisms in the modulation of the neurotrophin BDNF in the rat prefrontal cortex following acute agomelatine administration. World J Biol Psychiatry. 2010;11:148–153. doi: 10.3109/15622970903447659. [DOI] [PubMed] [Google Scholar]
- Molteni R, Macchi F, Zecchillo C, Dell'agli M, Colombo E, Calabrese F, et al. Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine. Eur Neuropsychopharmacol. 2013;23:1645–1655. doi: 10.1016/j.euroneuro.2013.03.008. [DOI] [PubMed] [Google Scholar]
- Monassier L, Laplante MA, Jaffre F, Bousquet P, Maroteaux L, de Champlain CJ. Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice. Hypertension. 2008;52:301–307. doi: 10.1161/HYPERTENSIONAHA.107.105551. [DOI] [PubMed] [Google Scholar]
- Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol. 2004;19:271–280. doi: 10.1097/01.yic.0000137184.64610.c8. [DOI] [PubMed] [Google Scholar]
- Morin LP. Serotonin and the regulation of mammalian circadian rhythmicity. Ann Med. 1999;31:12–33. doi: 10.3109/07853899909019259. [DOI] [PubMed] [Google Scholar]
- Morley-Fletcher S, Mairesse J, Soumier A, Banasr M, Fagioli F, Gabriel C, et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl) 2011;217:301–313. doi: 10.1007/s00213-011-2280-x. [DOI] [PubMed] [Google Scholar]
- Moutsimilli L, Farley S, Dumas S, El Mestikawy S, Giros B, Tzavara ET. Selective cortical VGLUT1 increase as a marker for antidepressant activity. Neuropharmacology. 2005;49:890–900. doi: 10.1016/j.neuropharm.2005.06.017. [DOI] [PubMed] [Google Scholar]
- Moyer RW, Kennaway DJ. Immunohistochemical localization of serotonin receptors in the rat suprachiasmatic nucleus. Neurosci Lett. 1999;271:147–150. doi: 10.1016/s0304-3940(99)00536-4. [DOI] [PubMed] [Google Scholar]
- Mukherjee S, Coque L, Cao JL, Kumar J, Chakravarty S, Asaithamby A, et al. Knockdown of CLOCK in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry. 2010;68:503–511. doi: 10.1016/j.biopsych.2010.04.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Musazzi L, Mallei A, Tardito D, Gruber SH, El KA, Racagni G, et al. Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression. J Psychiatr Res. 2010a;44:511–520. doi: 10.1016/j.jpsychires.2009.11.008. [DOI] [PubMed] [Google Scholar]
- Musazzi L, Milanese M, Farisello P, Zappettini S, Tardito D, Barbiero VS, et al. Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS ONE. 2010b;5:e8566. doi: 10.1371/journal.pone.0008566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Navailles S, Moison D, Ryczko D, Spampinato U. Region-dependent regulation of mesoaccumbens dopamine neurons in vivo by the constitutive activity of central serotonin2C receptors. J Neurochem. 2006;99:1311–1319. doi: 10.1111/j.1471-4159.2006.04188.x. [DOI] [PubMed] [Google Scholar]
- Norman TR, Cranston I, Irons JA, Gabriel C, Dekeyne A, Millan MJ, et al. Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: a comparison to melatonin and to the 5-HT(2c) antagonist, S32006. Eur J Pharmacol. 2012;674:27–32. doi: 10.1016/j.ejphar.2011.10.010. [DOI] [PubMed] [Google Scholar]
- O'Mahony SM, Bulmer DC, Coelho AM, Fitzgerald P, Bongiovanni C, Lee K, et al. 5-HT(2B) receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain-gut axis dysfunction. Neurogastroenterol Motil. 2010;22:573–578. doi: 10.1111/j.1365-2982.2009.01432.x. [DOI] [PubMed] [Google Scholar]
- Paizanis E, Renoir T, Lelievre V, Saurini F, Melfort M, Gabriel C, et al. Behavioural and neuroplastic effects of the new-generation antidepressant agomelatine compared to fluoxetine in glucocorticoid receptor-impaired mice. Int J Neuropsychopharmacol. 2010;13:759–774. doi: 10.1017/S1461145709990514. [DOI] [PubMed] [Google Scholar]
- Palucha A, Pilc A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther. 2007;115:116–147. doi: 10.1016/j.pharmthera.2007.04.007. [DOI] [PubMed] [Google Scholar]
- Papp M, Gruca P, Boyer PA, Mocaer E. Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology. 2003;28:694–703. doi: 10.1038/sj.npp.1300091. [DOI] [PubMed] [Google Scholar]
- Papp M, Litwa E, Gruca P, Mocaer E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol. 2006;17:9–18. doi: 10.1097/01.fbp.0000181601.72535.9d. [DOI] [PubMed] [Google Scholar]
- Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:250–272. doi: 10.1196/annals.1300.016. [DOI] [PubMed] [Google Scholar]
- Pei Q, Zetterstrom TS, Sprakes M, Tordera R, Sharp T. Antidepressant drug treatment induces Arc gene expression in the rat brain. Neuroscience. 2003;121:975–982. doi: 10.1016/s0306-4522(03)00504-9. [DOI] [PubMed] [Google Scholar]
- Pepin MC, Pothier F, Barden N. Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol Pharmacol. 1992a;42:991–995. [PubMed] [Google Scholar]
- Pepin MC, Pothier F, Barden N. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature. 1992b;355:725–728. doi: 10.1038/355725a0. [DOI] [PubMed] [Google Scholar]
- Perez J, Mori S, Caivano M, Popoli M, Zanardi R, Smeraldi E, et al. Effects of fluvoxamine on the protein phosphorylation system associated with rat neuronal microtubules. Eur Neuropsychopharmacol. 1995;5(Suppl):65–69. doi: 10.1016/0924-977x(95)00024-j. [DOI] [PubMed] [Google Scholar]
- Pickard GE, Rea MA. Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms. Biol Cell. 1997;89:513–523. doi: 10.1016/s0248-4900(98)80007-5. [DOI] [PubMed] [Google Scholar]
- Pitrosky B, Kirsch R, Malan A, Mocaer E, Pevet P. Organization of rat circadian rhythms during daily infusion of melatonin or S20098, a melatonin agonist. Am J Physiol. 1999;277:R812–R828. doi: 10.1152/ajpregu.1999.277.3.R812. [DOI] [PubMed] [Google Scholar]
- Qi X, Lin W, Li J, Li H, Wang W, Wang D, et al. Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis. 2008;31:278–285. doi: 10.1016/j.nbd.2008.05.003. [DOI] [PubMed] [Google Scholar]
- Quera Salva MA, Vanier B, Laredo J, Hartley S, Chapotot F, Moulin C, et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int J Neuropsychopharmacol. 2007;10:691–696. doi: 10.1017/S1461145707007754. [DOI] [PubMed] [Google Scholar]
- Racagni G, Popoli M, Molteni R, Musazzi L, Calabrese F, Tardito D, et al. Mode of action of agomelatine: synergy between melatonergic and 5-HT2C receptors. World J Biol Psychiatry. 2011;12:574–587. doi: 10.3109/15622975.2011.595823. [DOI] [PubMed] [Google Scholar]
- Rainer Q, Xia L, Guilloux JP, Gabriel C, Mocaer E, Hen R, et al. Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety. Int J Neuropsychopharmacol. 2012;15:321–335. doi: 10.1017/S1461145711000356. [DOI] [PubMed] [Google Scholar]
- Reagan LP, Reznikov LR, Evans AN, Gabriel C, Mocaer E, Fadel JR. The antidepressant agomelatine inhibits stress-mediated changes in amino acid efflux in the rat hippocampus and amygdala. Brain Res. 2012;1466:91–98. doi: 10.1016/j.brainres.2012.05.039. [DOI] [PubMed] [Google Scholar]
- Redman JR, Francis AJ. Entrainment of rat circadian rhythms by the melatonin agonist S-20098 requires intact suprachiasmatic nuclei but not the pineal. J Biol Rhythms. 1998;13:39–51. doi: 10.1177/074873098128999907. [DOI] [PubMed] [Google Scholar]
- Redman JR, Guardiola-Lemaitre B, Brown M, Delagrange P, Armstrong SM. Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms. Psychopharmacology (Berl) 1995;118:385–390. doi: 10.1007/BF02245938. [DOI] [PubMed] [Google Scholar]
- Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. 2007;104:6406–6411. doi: 10.1073/pnas.0609625104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schmelting B, Corbach-Sohle S, Kohlhause S, Schlumbohm C, Flugge G, Fuchs E. Agomelatine in the tree shrew model of depression: effects on stress-induced nocturnal hyperthermia and hormonal status. Eur Neuropsychopharmacol. 2014;24:437–447. doi: 10.1016/j.euroneuro.2013.07.010. [DOI] [PubMed] [Google Scholar]
- Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci. 2002;22:3251–3261. doi: 10.1523/JNEUROSCI.22-08-03251.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Soumier A, Banasr M, Lortet S, Masmejean F, Bernard N, Kerkerian-Le-Goff L, et al. Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology. 2009;34:2390–2403. doi: 10.1038/npp.2009.72. [DOI] [PubMed] [Google Scholar]
- Steardo L, Monteleone P, Trabace L, Cannizzaro C, Maj M, Cuomo V. Serotonergic modulation of rat pineal gland activity: in vivo evidence for a 5-Hydroxytryptamine(2C) receptor involvement. J Pharmacol Exp Ther. 2000;295:266–273. [PubMed] [Google Scholar]
- Tajes OM, Pelegri GC, Vilaplana HJ, Pallas LM, Camins EA. An evaluation of the neuroprotective effects of melatonin in an in vitro experimental model of age-induced neuronal apoptosis. J Pineal Res. 2009;46:262–267. doi: 10.1111/j.1600-079X.2008.00656.x. [DOI] [PubMed] [Google Scholar]
- Takahashi JS. Finding new CLOCK components: past and future. J Biol Rhythms. 2004;19:339–347. doi: 10.1177/0748730404269151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taliaz D, Stall N, Dar DE, Zangen A. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry. 2010;15:80–92. doi: 10.1038/mp.2009.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taliaz D, Haramati S, Chen A, Zangen A. 2011. The role of brain-derived neurotrophic factor in the effect of antidepressant treatments. Society for Neuroscience Nov. 12–16, Washington DC: p 904.07 [itinerary planner]
- Tang SW, Helmeste D, Leonard B. Is neurogenesis relevant in depression and in the mechanism of antidepressant drug action? A critical review. World J Biol Psychiatry. 2012;13:402–412. doi: 10.3109/15622975.2011.639800. [DOI] [PubMed] [Google Scholar]
- Tardito D, Milanese M, Bonifacino T, Musazzi L, Grilli M, Mallei A, et al. Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways. BMC Neurosci. 2010;11:68. doi: 10.1186/1471-2202-11-68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tordera RM, Pei Q, Sharp T. Evidence for increased expression of the vesicular glutamate transporter, VGLUT1, by a course of antidepressant treatment. J Neurochem. 2005;94:875–883. doi: 10.1111/j.1471-4159.2005.03192.x. [DOI] [PubMed] [Google Scholar]
- Tordera RM, Totterdell S, Wojcik SM, Brose N, Elizalde N, Lasheras B, et al. Enhanced anxiety, depressive-like behaviour and impaired recognition memory in mice with reduced expression of the vesicular glutamate transporter 1 (VGLUT1) Eur J Neurosci. 2007;25:281–290. doi: 10.1111/j.1460-9568.2006.05259.x. [DOI] [PubMed] [Google Scholar]
- Tuma J, Strubbe JH, Mocaer E, Koolhaas JM. Anxiolytic-like action of the antidepressant agomelatine (S 20098) after a social defeat requires the integrity of the SCN. Eur Neuropsychopharmacol. 2005;15:545–555. doi: 10.1016/j.euroneuro.2005.02.004. [DOI] [PubMed] [Google Scholar]
- Turek FW. From circadian rhythms to CLOCK genes in depression. Int Clin Psychopharmacol. 2007;22(Suppl. 2):S1–S8. doi: 10.1097/01.yic.0000277956.93777.6a. [DOI] [PubMed] [Google Scholar]
- Turek FW, Scarbrough K, Penev P, Labyak S, Valentinuzzi VS, Van Reeth O. Aging of the mammalian circadian system. In: Takahashi JS, Turek FW, Moore RY, editors. Circadian Clocks. New York: Kluwer Academic/Plenum Publishers; 2001. pp. 292–317. [Google Scholar]
- Uezato A, Meador-Woodruff JH, McCullumsmith RE. Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia. Bipolar Disord. 2009;11:711–725. doi: 10.1111/j.1399-5618.2009.00752.x. [DOI] [PubMed] [Google Scholar]
- Van Reeth O, Olivares E, Zhang Y, Zee PC, Mocaer E, Defrance R, et al. Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters. Brain Res. 1997;762:185–194. doi: 10.1016/s0006-8993(97)00382-x. [DOI] [PubMed] [Google Scholar]
- Van Reeth O, Olivares E, Turek FW, Granjon L, Mocaer E. Resynchronisation of a diurnal rodent circadian clock accelerated by a melatonin agonist. Neuroreport. 1998;9:1901–1905. doi: 10.1097/00001756-199806010-00043. [DOI] [PubMed] [Google Scholar]
- Van Reeth O, Weibel L, Olivares E, Maccari S, Mocaer E, Turek FW. Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1582–R1591. doi: 10.1152/ajpregu.2001.280.5.R1582. [DOI] [PubMed] [Google Scholar]
- Varcoe TJ, Salked M, Mocaer E, Seguin L, Kennaway DJ. Effects of chronic agomelatine administration on the expression of a panel of genes in various brain areas of rats. Eur Neuropsychopharmacol. 2009;19:S440. [Google Scholar]
- Wang LM, Dragich JM, Kudo T, Odom IH, Welsh DK, O'Dell TJ, et al. Expression of the circadian CLOCK gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour. ASN Neuro. 2009;1:139–152. doi: 10.1042/AN20090020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watts SW, Fink GD. 5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats. Am J Physiol. 1999;276:H944–H952. doi: 10.1152/ajpheart.1999.276.3.H944. [DOI] [PubMed] [Google Scholar]
- Weibel L, Turek FW, Mocaer E, Van Reeth O. A melatonin agonist facilitates circadian resynchronization in old hamsters after abrupt shifts in the light-dark cycle. Brain Res. 2000;880:207–211. doi: 10.1016/s0006-8993(00)02806-7. [DOI] [PubMed] [Google Scholar]
- Weil ZM, Hotchkiss AK, Gatien ML, Pieke-Dahl S, Nelson RJ. Melatonin receptor (MT1) knockout mice display depression-like behaviors and deficits in sensorimotor gating. Brain Res Bull. 2006;68:425–429. doi: 10.1016/j.brainresbull.2005.09.016. [DOI] [PubMed] [Google Scholar]
- Werry TD, Loiacono R, Sexton PM, Christopoulos A. RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacol Ther. 2008;119:7–23. doi: 10.1016/j.pharmthera.2008.03.012. [DOI] [PubMed] [Google Scholar]
- Wirz-Justice A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry. 1999;46:445–453. doi: 10.1016/s0006-3223(99)00125-0. [DOI] [PubMed] [Google Scholar]
- Ying SW, Rusak B, Delagrange P, Mocaer E, Renard P, Guardiola-Lemaitre B. Melatonin analogues as agonists and antagonists in the circadian system and other brain areas. Eur J Pharmacol. 1996;296:33–42. doi: 10.1016/0014-2999(95)00684-2. [DOI] [PubMed] [Google Scholar]
- Ying SW, Rusak B, Mocaer E. Chronic exposure to melatonin receptor agonists does not alter their effects on suprachiasmatic nucleus neurons. Eur J Pharmacol. 1998;342:29–37. doi: 10.1016/s0014-2999(97)01443-x. [DOI] [PubMed] [Google Scholar]
- Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeiffer B, et al. Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem. 1992;35:1484–1486. doi: 10.1021/jm00086a018. [DOI] [PubMed] [Google Scholar]
- Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA. Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology. 2010;58:465–473. doi: 10.1016/j.neuropharm.2009.09.005. [DOI] [PubMed] [Google Scholar]