Table 1.
Agomelatine in Mood and Anxiety Conditions and More. Current Literature Evidences in Pre-Clinical and/or Animal Model Studies
| Author, Date | Sample | Condition | Method | N Subjects | Dose/Range | Results | |
|---|---|---|---|---|---|---|---|
| Table 1 part a | |||||||
| Conboy et al., (2009) | Animal model (murine) | RAWM stress-induced memory impairment | RAWM stress-model: 4 arms: vehicle-no stress, vehicle-stress, agomelatine-no-stress & agomelatine-stress | 20 adult caves, 4 groups (5 subjects each) | Agomelatine 10mg/kg or vehicle 1mg/kg 1% hydroxyethylcellulose | Agomelatine blocked the predator stress-induced impairment of spatial memory. Both stressed and non-stressed agomelatine-treated rats showed an increase in the ventral hyppocampal expression of synaptic Neural Cell Adhesion Molecule (NCAM) | |
| Gressens et al. (2008) | Animal model (murine) | Periventricular leukomalacia and cerebral palsy model (induced by ibotenate injections) | Intracerebral injection in newborn mice of ibotenate (glutamate analogue) to develop human periventricular leukomalacia. Melatonin (already shown to have neuroprotective effects in mouse model) was compared to agomelatine to investigate the neuroprotective effects of the latter drug. | Swiss pups (unspecified number) | 10µg ibotenate were injected into developing mouse brains, inducing glutamate NMDA and metabotropic receptors activation. | Although agomelatine and melatonin did not prevent the initial appearance of white matter lesions, they did promote secondary lesions repair when given within the first 2h following the excitotoxic insult (up to 8h later for agomelatine) | |
| BertainaAnglade et al. (2006) | Animal model (murine) | Animal learned helplessness model | Stress response levels were recorded after pretreatment with agomelatine, melatonin, SB-242084 (selective 5-HT2c antagonist) or agomelatine + S22153 (melatonin receptor antagonist), compared to imipramine | 40 (10 per group) wistar rats | Agomelatine 2, 10, 50, 100 mg/kg; melatonin 2, 10, 50 mg/kg; SB-242084 0.31, 1.25, 5, 20 mg/kg; S22153 20 mg/kg; imipramine 64 mg/kg | Pretreatment with agomelatine, as with imipramine, decreased the number of escape failures, reflecting an antidepressant-like properties | |
| Loiseau et al. (2006) | Animal model (murine) | Animal model of anxiety | Rats behavior was monitored in the punished drinking test, the safety signal withdrawal operant paradigm, the elevated plus maze and hypophagia-induced novelty, after the administration of agomelatine or melatonin or agomelatine+diazepam or melatonin+diazepam | Unspecified n. | Agomelatine 20-40 mg/kg; melatonin 20-80mg/kg; diazepam 0.25 mg/kg | Agomelatine displayed a pattern of anxiolytic activity on its own (increasing the number of foot shocks received by rats, but non enhancing food consumption in unfamiliar environment); furthermore it potentiated the anxiolytic effects of diazepam; melatonin was less active | |
| Papp et al. (2006) | Animal model (murine) | Elevated plus maze, vogel, conditioned footshock-induced ultrasonic vocalization tests. | Monitoring of rats after the morning and evening administration of agomelatine, melatonin, diazepam, buspirone or vehicle in anxiety model caves | 16 (8+8) wistar rats + 8 sprague-dawley rats | Agomelatine 10, 20, 50, 75, 100, 125 mg/kg; melatonin 10, 20, 50 and 75 mg/kg; diazepam 2.5 and 5.0 mg/kg; buspirone 2.5 mg/kg; vehicle (1% hydroxyhethylcellulose) 1 ml/kg | Agomelatine displayed a pattern of anxiolytic activity resembling that of diazepam (but without sedative properties) and buspirone, while melatonin was far less active | |
| Table 1 part b | |||||||
| Loiseau et al. (2005) | Animal model (murine) | Animal model of depression (impulsive-related behavior) | Rats were trained in a T-maze and allowed to choose between two magnitudes of reward: immediate but small reward (two pellets) vs. 25-s delayed but large reward (ten pellets); rats behavior was examined after the administration of agomelatine, GR205171 (substance P receptor antagonist) and melatonin, in comparison to positive controls clomipramine and fluvoxamine | 10 rats per group, wistar rats | Agomelatine 10 and 30 mg/kg; GR205171 10 and 30 mg/kg; melatonin 3 and 10 mg/kg; clomipramine 8 mg/kg; fluvoxamine 4 mg/kg; vehicle (tween 80) | As clomipramine and fluvoxamine, agomelatine and GR205171 significantly increased the number of choices of the large-but-delayed reward. These results suggest that agomelatine enhances rats tolerance to delay gratification, an effect which may reflect its ability to improve impulse control | |
| Barden et al. (2005) | Animal model (murine) | Transgenic mouse model of the neuroendocrine characteristics of depression (low glucocorticoid receptor functioning) | Behavioral changes (porsolt forced swim test and elevated plus maze test), body temperature and ACTH and corticosterone levels were analyzed in transgenic mice after the administration of agomelatine, melatonin, desipramine or vehicle | 185 transgenic mice (bearing the glucocorticoid receptor antisense construct) and 115 non-transgenic mice (controls) | Agomelatine 10 mg/kg; melatonin 10 mg/kg; desipramine 10 mg/kg; vehicle (hydroxyethylcellulose 1%) | Agomelatine was effective in reversing the transgenic mouse behavioral changes, as well as desipramine or melatonin; agomelatine, but not imipramine, accelerated resynchronization of transgenic mouse circadian cycles of temperature and activity (this effect of agomelatine was more rapid than that of melatonin); no changes on concentrations of corticosterone and ACTH | |
| Millan et al. (2005) | Animal model (murine) | 6 different stress-induction models | Anxiolytic profile of agomelatine was compared with clorazepate and SB243,213 (selective 5-HT2c receptor antagonist) through a combined neurochemical and behavioral approach | Wistar rats and NMRI mice, unspecified number | Agomelatine, 0.63 to 80 mg/kg vs. melatonin (2.5-160 mg/kg) vs. SB243,213 (0.01-40 mg/kg) vs. clorazepate (0.63-40 mg/kg) vs. vehicle | The anxiolytic profile of agomelatine differs from that of benzodiazepines from which it may also be distinguished by its contrasting influence on cortico-limbic monoaminergic pathways | |
| Tuma et al. (2005) | Animal model (murine) | Animal model of anxiety (social defeat) | SCN-lesioned and non lesioned rats, subjected at a social defeat by an aggressive opponent | Unspecified n. | Agomelatine – variable doses | Agomelatine caused a clear reduction of the social defeat induced behavioral consequences only in the non lesioned rats, indicating that the anxiolytic -like action of agomelatine requires the integrity of the SCN | |
| Bourin et al., (2004) | Animal model (murine) | Animal model of depression | Forced swimming-test (FTS) in differently treated rodents (rats and mice). | 10 mices per group (4) and 6 rats per group (4) | Melatonin (4, 8, 16, 32, 64 mg/Kg) vs imipramine (64 mg/Kg, 8mg/Kg), fluoxetine (16mg/kg). | Antidepressant efficacy shown | |
| Table 1 part c | |||||||
| Hanoun et al. (2004) | Animal model (murine) | Animal model of depression | Binding/electrophysiological, comparative study on the 5-HT1A modulation by SSRI (fluoxetine) vs agomelatine | 13+(5+5)+(5+5) rats | Agomelatine 10mg/kg/day vs melatonin (10mg/kg/day) and agomelatine (50mg/Kg/day) vs fluoxetine (5mg/kg.day) | Agomelatine Antidepressant effect is not related to 5-HT1A modulation (as expected for other AD classes) | |
| Chagraoui et al. (2003) | Animal model (murine) | Dose-dependent effects of agomelatine in preventing penile erections in rats induced by 5-HT2c receptor agonists | Penile erections were measured in rats after the injection of the 5-HT2c agonists ( mCPP and Ro 60-0175), with or without agomelatine (and other melatonin derivates) pretreatment | 80-160 wistar rats | Agomelatine 1.25-40 mg/kg; melatonin 1.25-40 mg/kg; mCPP 0.75 mg/kg; Ro 60-0175 2.5 mg/kg | Agomelatine, but not melatonin, dose-dependently decreased mCPP- and Ro 60-0175- induced penile erections in rats, most probably due to its 5-HT2c receptor antagonism | |
| Millan et al. (2003) | Animal model (murine) | Binding affinities, in vivo, evaluation study | Antagonism at 5-HT2C receptors and blockade was evaluated with in vivo receptor binding assays and measures | Wistar rats (unspecified number) | Agomelatine, 0.16 to 80 mg/kg vs. melatonin (2.5-40 mg/kg) | In contrast to melatonin, agomelatine behaves as an antagonist at 5-HT2c receptors, increasing extracellular levels of DA and NA in FCX and accelerating the firing rate of adrenergic cell bodies in the locus coeruleus; hence enhancing the activity of fronto-cortical DA-ergic and adrenergic pathways | |
| Papp et al. (2003) | Animal model (murine) | Animal model of depression (chronic mild stress) | Sucrose test in rats subjected to the chronic stress procedure (food and water deprivation; 45° cage tilt; intermittent illumination; soiled cage; low intensity stroboscopic illumination) after evening or morning administration of agomelatine, melatonin, imipramine, fluoxetine or vehicle | 336 wistar rats | Agomelatine 10 and 50 mg/kg; melatonin 10 and 50mg/kg; imipramine 10 mg/kg; fluoxetine 10 mg/kg; vehicle (1% hydroxyethylcellulose) 1 ml/kg | Antidepressant-like activity of agomelatine was shown to be independent on the time of drug administration; the efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than melatonin’s one | |
| Tuma et al., (2001) | Animal model (murine) | Continuous dark exposure with consequent phase shift in circadian pacemaker | The free-running body temperature and activity rhythms were studied by gradual phase advances of the start of activity phase | Rats (various sp.) | Agomelatine up to 20mg/kg/day | Agomelatine treatment resulted in prolonged overstimulation of melatonin receptors, attenuating the effects of light on the circadian timing system. | |
| Van Reeth et al., (2001) | Animal model (murine) | Age-related changes in circadian response to environmental stimuls | Young and older hamsters fed with melatonin or its agonist agomelatine | 12+14 young (8 wk old) and 12+14 old (10 mo) hamsters | Variable doses | 6 of 7 young hamsters fed with agomelatine showed large phase advance vs only 2 (of 8) old controls | |
| Table 1 part d | |||||||
| Chu et al. (2000) | Animal model (murine) | Post-mortem evaluation of DA-ergic and PRL act. on TIDA neurons | Simultaneous determination of serum PRL and DOPAC levels in the median eminence (as indices for TIDA neuronal activity) in ovariectomized, estrogen-treated rats after time-dependent injections of melatonin, agomelatine, S-20928 or vehicle. | 50 sprague-dawley rats | Agomelatine 1 mg/kg; melatonin 0.01-1 mg/kg; S-20928 1 mg/kg | Melatonin and agomelatine exerts an inhibitory effect on PRL secretion by stimulating the TIDA neurons | |
| Weibel et al. (2000) | Animal model (murine) | Circadian resynchronization in old hamsters after abrupt shifts in the light-dark cycle | Running-wheel activity was monitored in two groups of hamsters (agomelatine-treated vs. control) subjected to an abrupt 8 h advance shift in the light-dark cycle (“jet-lag” paradigm) | 24 golden hamsters | Agomelatine 20 mg/kg | Agomelatine accelerated by 25% resynchronization of the circadian rhythm in hamsters to the new light-dark cycle | |
| Pitrosky et al. (1999) | Animal model (murine) | Organization of rat circadian rhythms during daily infusion of melatonin or agomelatine | Running-wheel activity, body temperature and general activity were monitored in rats in constant darkness during a period of daily infusions of melatonin or agomelatine for 1, 8 or 16 h | 110 long-evans rats | Agomelatine 50 and 100 microg/h; melatonin 50 and 100 microg/h | Agomelatine and melatonin entrained the free-running circadian rhythms of rats | |
| Ying et al., (1998) | Animal model (murine) | In vivo electrophysiological monitoring of SCN activity | Male Syrian hamsters were chronically exposed to melatonin and agomelatine to assess wherever this could influence later response of SCN receptorial activity | 50 caves in four groups: vehicle (2), melatonin and agomelatine | Agomelatine at 1mg/kg | Chronic SCN melatonin receptor exposure to agomelatine does not alter their effects on suprachiasmatic nucleus neurons | |
| Masson-pevet et al. (1998) | Animal model (murine) | Binding studies by quantitative autoradiography | Record of the effects of agomelatine, S-20928 and melatonin on melatonin receptors in the rat pars tuberalis | Unspecified n. | Agomelatine – variable doses | Agomelatine was able to down-regulate melatonin receptors in the rat pars tuberalis | |
| Mauriño et al. (1998) | Human blood mononuclear cells | Binding studies | Binding studies and cytokine determinations on human blood mononuclear cells after the administration of agomelatine (specific membrane receptor agonist), CGP 52608 (RZR/ROR nuclear receptor agonist) and melatonin (membrane and nuclear receptors agonist) | Unspecified n. | Agomelatine–variable doses | While melatonin and CGP 52608 increased IL2 and IL6 production (due to their activity on nuclear receptor), agomelatine did not stimulate cytokine production | |
| Redman and Francis (1998) | Animal model (murine) | Pineal gland taxotomy comparative models | Locomotor activity and body temperature rhythms were examined prior and after the injection of agomelatine or vehicle to assess the role of the suprachiasmatic nuclei (SCN) and of the pineal gland in the entrainment of circadian rhythms by agomelatine | 52 long-evans hooded rats | Agomelatine 1-10 mg/kg; vehicle (DMSO 50%) | Entrainment of circadian rhythms by agomelatine requires intact suprachiasmatic nuclei but not the pineal gland | |
| Table 1 part e | |||||||
| Van Reeth et al., (1998) | Animal model (murine) | Motor/ general activity reduction (depression) by dark prolonged exposure | “jet-lag” paradigms involving phase shifts in light-dark (LD) cycle, induced to investigate the effects of S-20098 on the circadian clock of diurnal rodents. | Male Arvichantis rodents (unspecified number) | Agomelatine (20mg/day/kg) on the day of shift and also on subsequent 6h or 8h shift paradigms. | In each condition, agomelatine accelerated by about 30% resynchronization to the new LD cycle. | |
| Wiley (1998) | Animal model (murine and monkeys) | Discrimination-reinforcement test in rats and monkeys | 10 adult Sprague-Dawley rats and 4 adult rhesus monkeys (Macaca mulatta) were trained to discriminate diazepam/ agomelatine and methohexital/agomelatine respectively | 10 adult rats and 4 adult monkeys | Diazepam 2.5mg/kg and methohexital 0.1mg/kg | Subjects preferred diazepam or non-melatonergic drugs to agomelatine, possibly indicating a non-addictive feature of the latter | |
| Tenn and Niles (1997) | Animal model (murine) | Modulation of rat dopaminergic activity by agomelatine | Apomorphine-induced turning behavior was monitored in 6-hydroxydopamine lesioned rats, after administration of agomelatine, agomelatine+flumazenil, agomelatine+bicuculline or vehicle; competition binding assays (binding affinities of agomelatine compared to clonazepam, diazepam, and melatonin at benzodiazepine/GABAA receptors in the striatum) | 34 sprague-dawley rats | Agomelatine 5 mg/kg; flumazenil 10 mg/kg; bicuculline 5nmol; apomorphine 0.25 mg/kg | Agomelatine inhibited apomorphine-induced turning In lesioned rats, showing an antidopaminergic effect (co-administration of flumazenil or bicuculline blocked this effects); agomelatine also inhibited [3H]diazepam binding striatal membrane; so the antidopaminergic action of agomelatine was mediated by BZ/GABAA receptors in the striatum | |
| Van Reeth et al., (1997) | Animal model (murine) | Motor/ general activity reduction (depression-like) by dark prolonged exposure | Sleep phase in mice and Syrian hamsters was investigated by Phase-Response-Curve (PRC) observation. Motor activity was evaluated by daily wheel revolutions record. | 45 (dark exposure and treatment varied among selected individuals) | Agomelatine (10mg/kg/day up to 20/25 mg/Kg/day, respectively in mice and hamsters) | Agomelatine showed dose-dependent phase shifting effects on all the used rodents, also improving motor activity. | |
| Martinet et al. (1996) | Animal model (murine) | Wheel-running activity monitoring in rats free-running in constant darkness | Dose- and concentration- dependent effects of agomelatine on entraining circadian rhythms of rats | 106 Long-evans rats | Agomelatine 0.5-10 mg/kg; melatonin 8 mg/kg; ipsapirone 8 mg/kg; vehicle (hydroxiethylcellulose 1% in H2O2) | Agomelatine was as effective as melatonin to entrain free-running rhythms; agomelatine showed dose-depended response from 2.5 to 10.0 mg/kg, and also a clear relation between entrainment and plasma concentration | |
| Grassi-Zucconi et al. (1995) | Animal model (murine) | Animal model of dysfunction of the sleep regulatory mechanisms | EEG recording in trypanosome- infected rats after administration of agomelatine, melatonin or vehicle (trypanosome infection in the rat reduced selectively the length of synchronized sleeps episodes) | 36 infected wistar rats and 17 non-infected wistar rats | Agomelatine 3 mg/kg; melatonin 3 mg/kg; vehicle (DMSO) | Agomelatine and melatonin restored a normal sleep pattern during the infection, increasing the length of synchronized sleep episodes | |
| Table 1 part f | |||||||
| Redman et al. (1995) | Animal model (murine) | Circadian resynchronization in rats after shifts in the light-dark cycle | Using 8h phase advance paradigm, the effects of daily-injections of agomelatine on the rat activity rhythms were compared with those of melatonin | Unspecified n. | Agomelatine 1.0-100 mg/kg | Agomelatine altered the direction of re-entrainment of rat activity rhythms in the same manner as melatonin; the effect was dose-dependent, with 100% of rats responding at a dose of 100 mg/kg | |
| Tobler et al. (1994) | Animal model (murine) | Reduced vigilance model in rats | The vigilance states, electroencephalogram power spectra (0.25-25.0 Hz), and cortical temperature were monitored in rats after the administration of agomelatine, melatonin or vehicle | 8 rats | Agomelatine 3 mg/kg; melatonin 3 mg/kg | Agomelatine and melatonin reduced the power density in non-rapid eye movement sleep in the low frequency range (1-8 Hz) but did not affect the vigilance states and brain temperature | |
| Armstrong et al. (1993) | Animal model (murine) | Animal model of delayed sleep-phase syndrome | Rats were held for 3 months in constant darkness; when they returned in a light-dark cycle, the onset of activity lags behind the onset of darkness by 3-4 h; rats activities was monitored after injected with agomelatine, melatonin or vehicle | 24 long-evans rats | Agomelatine 1 and 3 mg/kg; melatonin 1 mg/kg; vehicle (dimethylsulphoxide 50%) | Agomelatine and melatonin phase advanced the onset activity toward the onset of darkness | |