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Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats
Abstract
In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.
... Rogóz et al. repeatedly showed that amantadine (20 mg/kg) decreased immobility time in rats in the FST. 37,38 In another series of studies, amantadine was co-administered with antidepressant drugs. ...
... 12 Studies evaluating the potential of amantadine to potentiate the antidepressant effects of monoaminergic antidepressants These studies tested the hypothesis that the co-administration of amantadine with established antidepressant drugs increases their effectiveness. Rogó z et al. 37,38,41,51 evaluated the effects of acute administration of amantadine (10 or 20 mg/kg) alone or combined with imipramine (5 and 10 mg/kg; serotonin and norepinephrine reuptake inhibitor), venlafaxine (10 and 20 mg/kg; serotonin and norepinephrine reuptake inhibitor), and fluoxetine (5 and 10 mg/kg; selective serotonin reuptake inhibitor) in the FST. When administered alone, all of these drugs, with the exception of fluoxetine, decreased immobility time in rats at the highest dose tested. ...
... 41 A series of studies have evaluated the effects of co-administration of amantadine (10 mg/kg) plus imipramine and fluoxetine on immunological parameters. 37,41,51,62 The co-administration of amantadine with antidepressants was also shown to increase the production of interleukin (IL)-10 (a cytokine with antiinflammatory action) and decrease the proinflammatory activity of macrophages. Amantadine administration alone also increased IL-10. ...
Objective:
Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression.
Methods:
PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)."
Results:
Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress.
Conclusion:
Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.
... Moryl et al. (1993) demonstrated that alone injection of memantine (5, 10 and 20 mg/kg) 24, 5 and 1 h before the FST dose-dependently decreased duration of immobility time in rats and induce antidepressant-like activity (Moryl et al., 1993). Rogoz et al. (2002) indicated that intraperitoneally injection of memantine (5 mg/kg but not 2.5 mg/kg) alone generate an antidepressant-like activity in the rats exposed FST as an appropriate behavioral model for discovering antidepressant activity in rats ( Rogóż et al., 2002). The results of their study showed that co-administration of memantine (5 mg/kg) with imipramine (5 and 10 mg/kg) and fluoxetine (5 mg/kg) and co-treatment of memantine (2.5 mg/kg) with venlafaxine (10 mg/kg) and fluoxetine (5 and 10 mg/kg) produce a significant more enhanced antidepressant effect than each of these drugs alone in the FST ( Rogóż et al., 2002). ...
... Rogoz et al. (2002) indicated that intraperitoneally injection of memantine (5 mg/kg but not 2.5 mg/kg) alone generate an antidepressant-like activity in the rats exposed FST as an appropriate behavioral model for discovering antidepressant activity in rats ( Rogóż et al., 2002). The results of their study showed that co-administration of memantine (5 mg/kg) with imipramine (5 and 10 mg/kg) and fluoxetine (5 mg/kg) and co-treatment of memantine (2.5 mg/kg) with venlafaxine (10 mg/kg) and fluoxetine (5 and 10 mg/kg) produce a significant more enhanced antidepressant effect than each of these drugs alone in the FST ( Rogóż et al., 2002). These findings suggesting combined treatment with traditional antidepressants and the NMDA receptor antagonist memantine may induce a more augmented antidepressant effect than treatment with antidepressants alone in a synergistic (hyperadditive) manner that may have particular importance for patients with treatment resistance depression ( Rogóż et al., 2002). ...
... The results of their study showed that co-administration of memantine (5 mg/kg) with imipramine (5 and 10 mg/kg) and fluoxetine (5 mg/kg) and co-treatment of memantine (2.5 mg/kg) with venlafaxine (10 mg/kg) and fluoxetine (5 and 10 mg/kg) produce a significant more enhanced antidepressant effect than each of these drugs alone in the FST ( Rogóż et al., 2002). These findings suggesting combined treatment with traditional antidepressants and the NMDA receptor antagonist memantine may induce a more augmented antidepressant effect than treatment with antidepressants alone in a synergistic (hyperadditive) manner that may have particular importance for patients with treatment resistance depression ( Rogóż et al., 2002). ...
A developing body of evidence indicates that disturbed glutamate neurotransmission especially through N-methyl-d-aspartate (NMDA) is central to the pathophysiology of major depressive disorder (MDD) and NMDA receptor antagonists have shown therapeutic potential in the MDD treatment. Memantine is an uncompetitive NMDA receptor antagonist, approved for treatment of Alzheimer's disease (AD) that in contrast to other NMDA receptor antagonists at therapeutic doses does not induce highly undesirable side effects. Neuroprotective properties and well tolerability of memantine have been attributed to its unique pharmacological features such as moderate affinity, rapid blocking kinetics and strongly voltage-dependency. In this review we summarized clinical trial evidence of antidepressant effectiveness of memantine and its mechanisms of action. Available data indicate contradictory findings relating to clinical efficacy suggesting further research is necessary in determining as to whether memantine will eventually be an advantageous therapy for MDD. Preclinical data proposed various neurobiological mechanisms underlying antidepressant-like properties of memantine that are responsible for synaptic plasticity and cell survival.
... Memantine has displayed antidepressant-like effects in the animal models (Moryl et al., 1993; Réus et al., 2010). Several studies have suggested that the combination of traditional antidepressant drugs and NMDA receptor antagonists such as, memantine, ketamine and amantadine may produce enhanced antidepressive effects in animal models, as well as in humans (Réus et al., 2011; Rogóz et al., 2007 Rogóz et al., , 2002). The cellular and molecular mechanisms underlie to the efficacy of this combination therapy in animal models of depression as well as in depressed patients remain unclear. ...
... However, positive effects were observed in higher doses of 5-HT reuptake inhibitors or when the test was performed in mice (Nixon et al., 1994). In addition, several studies have shown that memantine has antidepressive-like effects in animal models of depression (Almeida et al., 2006; Rogóz et al., 2002; Skuza and Rogóz, 2002). Previous studies also have demonstrated that memantine in combination with the traditional antidepressant drugs, such as fluoxetine and venlafaxine enhances the antidepressant effect in Porsolt's test (Moryl et al., 1993; Rogóz et al., 2002). ...
... In addition, several studies have shown that memantine has antidepressive-like effects in animal models of depression (Almeida et al., 2006; Rogóz et al., 2002; Skuza and Rogóz, 2002). Previous studies also have demonstrated that memantine in combination with the traditional antidepressant drugs, such as fluoxetine and venlafaxine enhances the antidepressant effect in Porsolt's test (Moryl et al., 1993; Rogóz et al., 2002). Moreover, Ferguson and Shingleton in one open label study showed that memantine improved depressive symptoms within 1 week and sustained maximal improvement from weeks 8–12 (Ferguson and Shingleton, 2007). ...
A developing body of data has drawn attention to the N-methyl-d-aspartate (NMDA) receptor antagonists as potential drugs for the treatment of major depressive disorder (MDD). We investigated the possibility of synergistic interactions between the antidepressant sertraline with the uncompetitive NMDA receptor antagonist, memantine. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with memantine and sertraline alone or in combination in rats. To this aim, rats were chronically treated with memantine (2.5 and 5 mg/kg) and sertraline (5 mg/kg) for 14 days once a day, and then exposed to the forced swimming test. The brain-derived neurotrophic factor (BDNF) levels were assessed in the hippocampus and prefrontal cortex in all groups by ELISA sandwich assay. Sertraline and memantine (2.5 mg/kg) alone did not have effect on the immobility time; however, the effect of sertraline was enhanced by both doses of memantine. Combined treatment with memantine and sertraline produced stronger increases in the BDNF protein levels in the hippocampus and prefrontal cortex. Our results indicate that co-administration of antidepressant memantine with sertraline may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. Antidepressant properties using the combination of memantine and sertraline could be attributed to increased levels of BDNF. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whereas limiting side effects.
... A literatura reporta ainda que antagonistas de receptores glutamatérgicos NMDA apresentam efeito tipo-antidepressivo sinérgico quando combinados com antidepressivos em modelos animais (Maj et al., 1992;Rogóz et al., 2002Rogóz et al., , 2004. Em específico, fortes evidências clínicas e pré-clínicas estão sugerindo que a suplementação realizada com o inibidor de receptor NMDA zinco apresenta efeito sinérgico e aditivo quando associada a antidepressivos tricíclicos e ISRSs (Kroczka et al., 2001;Szewczyk et al., 2002;Nowak et. ...
... Além disso, a literatura reporta que o zinco inibe a enzima óxido nítrico sintase, dentre outros efeitos no SNC (Mittal et al., 1995;Choi e Koh, 1998;Rosa et al., 2003). Similarmente ao zinco, outros antagonistas do receptor NMDA tais como a amantadina, memantina, neramexana (Rogóz et al., 2002), ACPC, AP-7, MK-801 (Trullas e Skolnick, 1990;Trullas et at., 1991;Maj et at., 1992;Skolnick et al., 1992;Rosa et al., 2003;Mantovani et al., 2002) e cetamina (Mantovani et al., 2002;Rosa et al., 2003;Garcia et al., 2008;Maeng et al., 2008) também apresentam efeito tipo-antidepressivo em modelos animais. Além disso, ensaios clínicos têm indicado que altos níveis de glutamato são observados no SNC de pacientes depressivos (Mathis et al., 1988;Altamura et al., 1993;Levine et al., 2000), bem como anormalidades nos receptores NMDA (Law e Deakin, 2001), sendo que antagonistas de receptores NMDA, como a cetamina (Berman et al., 2000;Zarate et al., 2006; Skolnick (1999) propôs que inibidores de receptores glutamatérgicos NMDA poderiam ser os antidepressivos do novo milênio (Skolnick, 1999). ...
... Além do zinco, outros antagonistas de receptor NMDA como memantina, amantadina, neramexana e MK-801 também produzem efeito sinérgico tipo-antidepressivo quando combinados com antidepressivos (Maj et al., 1992;Rogóz et al., 2002Rogóz et al., , 2004. Nós sugerimos que o bloqueio dos receptores NMDA através da administração de antagonistas NMDA melhora o efeito de drogas antidepressivas clássicas. ...
O efeito tipo-antidepressivo do zinco vem sendo demonstrado em alguns modelos animais de depressão. No presente estudo, cloreto de zinco (ZnCl2) foi administrado, sozinho ou em combinação com diferentes antidepressivos, por via oral (p.o.), em camundongos, e a resposta comportamental no teste de suspensão da cauda (TSC), teste preditivo de atividade antidepressiva, e no teste do campo aberto foi investigada. ZnCl2 administrado nas doses de 10 e 30 mg/kg, p.o., 60 minutos antes dos testes comportamentais, reduziu o tempo de imobilidade no TSC, sem afetar a atividade locomotora no teste do campo aberto. Além disso, ZnCl2 (30 mg/kg, p.o.) apresentou efeito tipo-antidepressivo quando foi administrado 30’ antes do TSC. Os antidepressivos fluoxetina, paroxetina, imipramina, desipramina e bupropiona produziram uma significativa redução no tempo de imobilidade no TSC nas doses de 10; 1; 1;1;10 mg/kg, p.o., respectivamente. O tratamento combinado de doses sub-efetivas de ZnCl2 (1 mg/kg) com doses sub-efetivas de fluoxetina (5 mg/kg), paroxetina (0,1 mg/kg), desipramina (0,1 mg/kg), imipramina (0,1 mg/kg), ou bupropiona (1 mg/kg) gerou uma significativa redução no tempo de imobilidade no TSC, quando comparado com grupos tratados com o veículo, ZnCl2 ou antidepressivos sozinhos. O tratamento com ZnCl2 e antidepressivos sozinhos ou em combinação não afetou a locomoção dos animais submetidos ao teste do campo aberto, exceto a desipramina que administrada sozinha reduziu a locomoção dos animais. O tratamento com desipramina (0,1 mg/kg) ou paroxetina (0,1 mg/kg) sozinhos reduziu o número de respostas de levantamento vertical (“rearings”) no teste do campo aberto. O tratamento com bupropiona (1 mg/kg) ou desipramina (0,1 mg/kg) sozinhos reduziu o número de respostas de auto-limpeza dos animais submetidos ao teste do campo aberto. Ainda, a administração combinada de ZnCl2 com bupropiona também diminuiu o número de respostas de auto-limpeza, condizente com um efeito semelhante a de benzodiazepínicos (ansiolíticos). Os resultados indicam, inicialmente, que o ZnCl2 administrado por via oral produz um efeito tipoantidepressivo no TSC. Além disso, efeitos sinérgicos da administração de ZnCl2 com antidepressivos em diferentes classes foi mostrado no TSC, sugerindo que uma melhora na terapia antidepressiva clássica ocorra quando o zinco é acrescentado ao tratamento realizado com antidepressivos. Ainda, a combinação de ZnCl2 com o inibidor da recaptação de dopamina bupropiona diminuiu o número de auto-limpeza de animais submetidos ao teste do campo aberto, sugerindo que esta combinação seja efetiva no tratamento de pacientes aonde a depressão coexista com a ansiedade.
... In rodent studies, memantine administered acutely in doses of 3-20 mg/kg exerted antidepressant effects in the FST (Almeida, Felisbino, López, Rodrigues, & Gabilan, 2006;Almeida, Souza, et al., 2006;R eus et al., 2010;Rogóz, Skuza, Maj, & Danysz, 2002;Skuza & Rogóz, 2003). In rats subjected to CMS, which presented with anhedonic behavior and with corticosterone and BDNF levels dysfunctions, memantine treatment reversed these alterations (R eus, Abelaira, et al., 2012). ...
... In rats subjected to CMS, which presented with anhedonic behavior and with corticosterone and BDNF levels dysfunctions, memantine treatment reversed these alterations (R eus, Abelaira, et al., 2012). The combination of memantine and classic antidepressants, such as imipramine, venlafaxine, and fluoxetine, produced synergistic antidepressant effects in rodents (Rogóz et al., 2002). Memantine's mechanism of action has been reported for many studies. ...
... Amantadine has been used since 1966 as an antiviral agent against influenza A viral infections and showed remarkable antidepressant efficacy in depressed patients infected with the Borna disease virus (Dietrich et al., 2000). In addition, this compound was shown to produce only mild antidepressant effects when administered alone, but was effective as an adjunctive therapy in combination with other antidepressants in both human and animal models (Rogóz et al., 2002(Rogóz et al., , 2007. Kubera et al. (2006) showed that exposure to an FST produced an increase in plasma corticosterone levels in rats, which was significantly attenuated by adjunctive therapy with imipramine and amantadine. ...
Major depressive disorder (MDD) affects approximately 121 million individuals globally and poses a significant burden to the healthcare system. Around 50–60% of patients with MDD respond adequately to existing treatments that are primarily based on a monoaminergic system. However, the neurobiology of MDD has not been fully elucidated; therefore, it is possible that other biochemical alterations are involved. The glutamatergic system and its associated receptors have been implicated in the pathophysiology of MDD. In fact, the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor, is a binding or modulation site for both classical antidepressants and new fast-acting antidepressants. Thus, this review aims to present evidence describing the effect of antidepressants that modulate NMDA receptors and the mechanisms that contribute to the antidepressant response.
... However, ketamine's psychotomimetic effects preclude its use as a chronic antidepressant (Berman et al., 2000). Another NMDA receptor antagonist, memantine, also displays antidepressant-like effects in preclinical studies, but, in contrast to ketamine, it is devoid of psychotomimetic effects (Almeida et al., 2006;Parsons et al., 1999;Rogóz et al., 2002;Skuza and Rogóz, 2003). ...
... This effect of memantine was dose-dependent and did not influence locomotor activity. Our data are consistent with previous reports that memantine exhibits antidepressant-like effects in various pharmacological tests, such as the forced swim test, the tail suspension test or during chronic mild stress (Réus et al., 2010;Réus et al., 2012;Rogóz et al., 2002;Skolnick et al., 2015;Tokita et al., 2012). Furthermore, we compared the effect of memantine administration to that of a classical antidepressant drug, imipramine. ...
... They showed that when fluoxetine was given alone no effect was observed but on combination with NMDA antagonist, it significantly reduced the immobility time. 26 The possible explanation to this is, that ketamine has high affinity for NMDA receptor, it also has less but potentially relevant affinity for µ (mu) opiates and weak antagonistic activity for dopamine transporter. 27 Additionally, NMDAR agent may potentially affect mood due to their secondary effect on monoamine and opiate. ...
Background: The present study was designed to investigate the effect of citalopram, ketamine, glycine and their combinations on animal models of depression. Methods: Swiss Albino male mice were subjected to chronic mild stress for 6 weeks for inducing depression, and randomly divided into different groups: citalopram (5 and 10 mg/kg), ketamine (17.5 and 35 mg/kg), glycine (50 and 100 mg/kg), ketamine (17.5 mg/kg) + citalopram (5 mg/kg) and ketamine (17.5 mg/kg) + glycine (50 mg/kg). Two behavioural tests were utilized for the assessment of depression, namely tail suspension test (TST) and forced swim test (FST). Immobility time was recorded for 6 min, before and after administration of drug. Results: Citalopram (10 mg/kg) administration caused significant decrease in the immobility time in TST model only but not in FST. Citalopram (5 mg/kg) and ketamine (17.5 mg/kg) caused insignificant decrease in immobility time in both the models. Moreover, ketamine in combination with Citalopram significantly reduced the immobility time in both the models. Glycine at a dose of 100 mg/kg (but not 50 mg/kg) significantly increased the immobility time in both the models as compared to control group. Further, ketamine when administered with glycine caused increase in the immobility time on both the paradigms, though insignificant. Conclusions: Ketamine demonstrated antidepressant like action in both TST and FST models. Moreover, it potentiated the antidepressant effect of citalopram that might be due to the role of NMDA receptors.
... Memantine reportedly improved cognitive deficits in mammalian AD mice models-APP23 and 5xFAD [15,41]. In addition, memantine rescued depressive behaviors in various mice models [42,[50][51][52]58]. Recently, we demonstrated that memantine rescues both cognitive deficits and depressive behaviors via adenosine 5′-triphosphate (ATP)-sensitive potassium (K ATP ) channel inhibition [41,42]. ...
Propolis is a complex resinous substance that is relevant as a therapeutic target for Alzheimer’s disease (AD) and other neurodegenerative diseases. In this study, we confirmed that propolis (Brazilian green propolis) further enhances the rescue of cognitive deficits by the novel AD drug memantine in APP-KI mice. In memory-related behavior tasks, administration of a single dose of propolis at 1–100 mg/kg p.o. significantly enhanced the rescue of cognitive deficits by memantine at 1 mg/kg p.o. in APP-KI mice. In in vitro studies, propolis significantly increased intracellular Ca²⁺ concentration and calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation in Kir6.2-overexpressed N2A cells treated with memantine. Propolis also significantly increased adenosine 5′-triphosphate (ATP) contents and CaMKII autophosphorylation, which was impaired in Aβ-treated Kir6.2-overexpressed N2A cells. Similarly, repeated administration of propolis at 100 mg/kg p.o. for 8 weeks further enhanced the rescue of cognitive deficits by memantine in APP-KI mice. Consistent with the rescued cognitive deficits in APP-KI mice, repeated administration of propolis markedly ameliorated memantine-dependent rescue of injured long-term potentiation (LTP) in APP-KI mice, concomitant with increased CaMKII autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in the hippocampal CA1 region. Furthermore, repeated administration of both memantine and propolis significantly restored the decreased ATP contents in the CA1 region of APP-KI mice. Finally, we confirmed that repeated administration of memantine at 1 mg/kg p.o. and propolis at 100 mg/kg p.o. for 8 weeks failed to restore the cognitive deficits in Kir6.2−/− mice. Our study demonstrates that propolis increases ATP contents and promotes the amelioration of cognitive deficits rescued by memantine via Kir6.2 channel inhibition in the CA1 region.
... 1. Given that, in addition to the above, the AD-like effects of conventional AD drugs are potentiated by NMDA antagonists [31][32][33], and that some of the behavioural effects of negative GABA-A modulators (e.g., PTZ, FG7142) are mediated by NMDA receptors [34][35][36][37][38][39][40][41], the question arises that is glutamate transmission involved (and how?) in the potentiation of effects of conventional ADs by partially inhibiting GABA-A receptor function (as in the above-mentioned studies using PIC or PTZ at low doses)? ...
The present perspective paper shortly and specifically addresses the issues of whether inhibition of GABA-A receptor-mediated synaptic transmission may be involved in antidepressant-like actions and the therapeutic effects of conventional antidepressant (AD) drugs, and whether the recent development of negative allosteric modulators (NAMs) of the alpha5-GABA-A receptor may constitute significant progress in our knowledge on the neurobiology and the treatment of depression.
... In our study, combination of ketamine with citalopram showed signifi cant reduction in the immobility time and increase in struggle time in both the models as compared to control group. This is attributed to synergistic activity of citalopram with ketamine as seen in earlier studies [28,32,33]. ...
... This is attributed to synergistic activity of citalopram with ketamine as seen in earlier studies [28,32,33]. Additionally, ketamine affect mood due to its interaction with monoamine and opiate systems [34][35][36]. ...
... All nine experimental studies conducted so far on animal models of depression have shown the antidepressant effect of memantine [18][19][20][21][22][23][24][25][26]. It is therefore surprising that most clinical trials carried out later failed to confirm the antidepressant effect of memantine in monotherapy and as an add-on treatment [13,27,30,31]. ...
The treatment of bipolar depression is hampered by the inadequate efficacy of antidepressants, moderate effect of mood stabilizers, and the side effects of some second-generation antipsychotics. There is limited evidence to date regarding the antidepressant effects of memantine in bipolar depression. The aim of the article was to provide a short review of preclinical and clinical studies on the antidepressant effect of memantine, and to present the case of a bipolar depression patient successfully treated with memantine. The described patient with bipolar disorder was unsuccessfully treated with two mood stabilizers. The addition of memantine at a dose of 20 mg/d to the treatment with lamotrigine and valproic acid resulted in a reduction in the severity of depression measured on the HDRS-17 scale by 35%, and by 47.1% after 7 weeks. The discussion presents experimental evidence for the antidepressant effect of memantine, as well as data from clinical trials in recurrent and bipolar depression. The presented case is the second report in the medical literature showing the antidepressant effect of memantine as an add-on treatment for bipolar depression. The described case and literature analysis indicate that memantine may be an effective and safe method of augmentation of mood stabilizing therapy in bipolar depression.
... Likewise, an acute administration of several NMDA receptor antagonists, including ketamine or its metabolite (2R,6R)hydroxynorketamine or Ro25-698, promoted antidepressant-like activities (Gideons et al., 2014;Talbot et al., 2016), notably in the NSF (Gideons et al., 2014;Zanos et al., 2016). Some studies revealed synergistic antidepressant-like effects of a combination of selective serotonin reuptake inhibitors and NMDA receptor antagonists (Maj et al., 1996;Rogoz et al., 2009;Rogoz et al., 2002). In this study, we investigated the differential effects of the chronic treatment with fluoxetine and the acute local administration of the GluN2B antagonist Ro25-6981 in the vDG alone or in combination in a mouse model of anxiety/depression in the NSF, as well as their differential neurochemical effects. ...
Les épisodes dépressifs caractérisés sont la première cause d’incapacité dans le monde d’après l’OMS. Les inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) sont la classe d’antidépresseurs la plus prescrite, mais ils ont un délai d’action retardé, non entièrement expliqué par la stimulation de la neurotransmission sérotoninergique. L’intégration des jeunes neurones issus de la neurogenèse adulte hippocampique dans le gyrus dentelé (GD) de l’hippocampe jouerait un rôle clef dans l’efficacité des ISRS. Nous nous sommes intéressés aux variations de neurotransmissions dans le GD ventral engendrées par l’intégration de ces nouveaux neurones après un traitement chronique avec la fluoxétine, grâce à un couplage de la microdialyse intracérébrale à des outils pharmacologiques et optogénétiques chez la souris. L’administration chronique de fluoxétine a engendré une diminution des transmissions glutamatergiques dans le GD. La sous-unité GluN2B du récepteur NMDA du glutamate des jeunes neurones jouant un rôle important dans les effets antidépresseurs, nous avons souhaité inhiber les jeunes neurones par l’administration locale dans le GD ventral d’un antagoniste sélectif de la sous-unité GluN2B du récepteur NMDA (Ro25-6981) après un traitement chronique avec la fluoxétine, produisant ainsi une libération des concentrations extracellulaires de glutamate et de GABA dans le GD. Enfin, la stimulation sélective des jeunes neurones par optogénétique a révélé une augmentation des concentrations extracellulaires de GABA dans le GD. Mes travaux de thèse apportent des éléments indirects et directs des effets neurochimiques des jeunes neurones. Ces effets neurochimiques constitueraient le lien entre les effets électrophysiologiques et comportementaux attribués aux jeunes neurones de l’hippocampe.
... On the other hand, ketamine showed signifi cant decrease in immobility time both in FST & TST models. This is similar to the study showing dose dependent decrease in immobility time by MK-801, ketamine & imipramine, but not by fl uoxamine [31]. This effect of ketamine in present study could probably be explained by an NMDA receptor antagonism. ...
... However, there is a drawback to this study as single doses of paroxetine (10 mg/kg) and NMDA antagonists (1 mg/kg CGP 40116, 40 mg/kg amantadine, 10 mg/kg budipine, 0.9 mg/kg ifenprodil) were used to produce these accelerated neurochemical changes. In view of this, during the preparation of this manuscript, a report by Rogoz et al (2002) investigated the possibility of synergistic interactions between three ADs at different doses [imipramine (5 and 10 mg/kg), venlafaxine (10 or 20 mg/kg) and fluoxetine (5 or 10 mg/kg)] with three non-competitive antagonists at different doses [amantadine ( 1 0 or 2 0 mg/kg), memantine (2.5 or 5 mg/kg) and neramexane (5 or 10 mg/kg)]. These authors report that most combinations resulted in synergistic AD-like effects in the FST. ...
It is widely accepted that the symptoms of depression are due, in part, to abnormal monoaminergic tone in the brain, primarily serotonin, noradrenaline and to a lesser extent dopamine. This constitutes the monoamine theory of depression. Antidepressants (ADs) work by increasing the extracellular concentration of monoamines at the synapse. Though, their mechanism is not fully understood, it has been suggested that chronic AD treatments can affect NMDA receptor function in the brain. Using in vivo microdialysis in freely moving rats, the effects of acute, 7-day subchronic and chronic doses of the ADs paroxetine and clomipramine treatment on the NMDA- evoked efflux of extracellular DA, 5-HT and their metabolites, DOPAC and 5-HIAA respectively in the frontal cortex were investigated. The duration of these effects after 48 hours and 14 days of drug cessation, and the effect of the co-administration of NMDA antagonists with paroxetine on monoamine levels and their metabolites was also investigated. Acute injection of paroxetine (10 and 20 mg/kg i.p.) did not affect dialysate DA or 5-HT content in the frontal cortex. Clomipramine at 10 and 20 mg/kg caused a decrease in extracellular DA without exerting any influence on dialysate 5-HT levels. Local infusion of 100μM NMDA into the frontal cortex decreased both extracellular DA and 5-HT levels in this region. 21 day treatment of rats with paroxetine and clomipramine increased 5-HT levels to 150% and 147% above basal levels respectively. The same treatment increased DA levels to 200% and 186% above basal levels. When NMDA infusion was preceded by a single injection of paroxetine/clomipramine no marked differences between NMDA and NMDA+paroxetine/clomipramine treated groups were observed. Subchronic (7-days) and chronic (21-days) treatment with paroxetine/clomipramine were able to abolish the NMDA-evoked decrease in dialysate DA and 5-HT levels. This effect lasted for a period of 48 hours but was abolished following a 14-day 'drug holiday'. This suggests that adaptive functional changes occur in NMDA receptor function during treatment with AD drugs. These results suggest that the NMDA receptor is subject to adaptive changes following chronic AD treatment. Interestingly, the co-administration of acute paroxetine with NMDA antagonists (amantadine, budipine, CGP 40116 and ifenprodil) causes an increase in extracellular 5-HT which may prove to have clinical implications.
... Several studies have demonstrated that blockade of NMDA receptors provokes antidepressant (-like) effects in both clinical and preclinical evaluations [20,21]. In this regard, it has been shown that co-administration of NMDA receptor antagonists potentiated the antidepressant effect of commercial drugs [22]. Ample evidence suggested that ketamine and memantine as NMDA receptor blockers exerted antidepressant effects [23,24]. ...
Background and Aim
Depression is a mood disorder with high global prevalence. Depression is associated with a reduction in the hippocampal volume and change in its neurotransmitters function. Trigonelline is an alkaloid with neuroprotective activity. The aim of this study was to investigate the possible role of N-methyl-D-aspartate (NMDA) receptor in the antidepressantlike effect of trigonelline considering histopathological modifications of the hippocampus.
Methods
60 Naval Medical Research Institute (NMRI) male mice were divided into 6 groups including group 1 (normal saline), groups 2, 3 and 4 (trigonelline at doses of 10, 50 and 100 mg/kg), group 5 (effective dose of trigonelline plus NMDA agonist), group 6 (sub-effective dose of trigonelline plus NMDA antagonist). Forced swimming test (FST) was used to assess depressive-like behavior. Hippocampi were separated under deep anesthesia and used for histopathological evaluation as well as NMDA receptor gene expression assessment.
Results
Trigonelline at doses of 10, 50 and 100 significantly reduced the immobility time in the FST in comparison to the control group. The administration of the sub-effective dose of trigonelline plus ketamine (a NMDA receptor antagonist) potentiated the effect of the subeffective dose of trigonelline. In addition, co-treatment of effective dose of trigonelline with NMDA mitigated the antidepressant-like effect of trigonelline. Trigonelline at doses of 50 and 100 mg/kg significantly increased the diameter of the CA1 area of the hippocampus.
Conclusion
Trigonelline showed an antidepressant-like effect in mice probably via attenuation of NMDA receptor activity and increase in the CA1 region of the hippocampus.
... Previous experiments have shown that memantine has synergist effects when used with antidepressant in the FST in rats. [33] Alike dextromethorphan memantine is a low-affinity NMDAR channel blocker, only after channel opening, it can enter the channel and block current flow. [34] Interestingly, magnesium ions reduce the affinity of memantine for NMDA receptor channels, and thus in the presence of physiological levels of Mg ++ ions, memantine displays approximately 10-fold selectivity for GluN1/GluN2C and GluN1/GluN2D receptors. ...
Introduction: Treatment with interferon-alpha (IFNa) can induce depression that is likely the result of its effect on the tryptophan-kynurenine pathway. Kynurenine passes through the blood–brain barrier and breaks to neurotoxic metabolites, such as quinolinic acid, with agonistic effect on N-methyl-D-aspartate receptor (NMDAR). Thus, tryptophan available for serotonin synthesis declines. The aim was to evaluate the effect of NMDAR antagonists on IFNa-induced depression in mice model of despair. Materials and Methods: The total immobility time in the forced swimming test (FST) was assessed as an indicator of depression in mice. Depression was induced by IFNa injection (16 × 105 IU/kg) for 6 consecutive days. The optimum dose of dextromethorphan, memantine, and dizocilpine (MK-801) was administered on the 7 th day following IFNa injection. Results: Immobility time in the FST was increased following IFNa injection (181 s ± 7 vs. control 122 s ± 10, P < 0.05) which indicated depression behavior. Dextromethorphan (15 mg/kg) and MK-801 (0.075 mg/kg) administration reduced the immobility time in IFNa-treated animals (57 s ± 14 and 46 s ± 6, respectively). Memantine (5 mg/kg) reduced the immobility time when it was administered alone but failed to decrease the immobility time induced by IFNa. The animals’ locomotor activity was normal in the experimented groups. Conclusion: Dextromethorphan and MK-801 inhibited IFNa-induced depression. Thus, at least part of IFNa depressive behavior is caused by NMDAR that is stimulated by the production of metabolites in the tryptophan-kynurenine pathway. Administrating NMDAR antagonists should be further evaluated for patients suffering from the neurologic side effects of IFNa. © 2019, Faculty of Pharmaceutical Sciences, Chulalongkorn University. All rights reserved.
... These data can use to predict the antidepressant activity of these drugs. [14,15] The antimanic effects of NMDA antagonists have been demonstrated in animal models, and case reports suggested that they may also be effective in controlling the manic and mixed phases of BD. [16,17] Although there are still no definitive findings in this regard, some studies have shown the efficacy of memantine as a strong strategy and even memantine monotherapy for acute manic/mixed episodes. [18] Memantine is a less complicated drug and is usually well tolerated; [19] therefore, it has been considered as an adjunctive strategy to treat BD. ...
Background
This study aimed to evaluate the efficacy of memantine in the acute treatment of geriatric with bipolar disorder (BD) hospitalized for mania.
Materials and Methods
This study conducted on 70 patients older than 60 years with BD in the acute phase of mania. Oral sodium valproate was prescribed in both groups. The intervention group received memantine tablet and the placebo group received a placebo tablet based on a same procedure. Severity of mania, cognitive changes, and quality of life (QoL) were assessed and recorded 4 and 8 weeks after the beginning of the study. The collected data were analyzed with SPSS (version 20) using independent samples t-test, analysis of variance in repeated observations, Chi-squared test, and Fisher's exact test.
Results
Mania severity score had no significant difference at the beginning of the study, but 4 and 8 weeks after the intervention, it was reduced significantly in both groups (P < 0.001) that was higher in memantine group (P = 0.038). The mean increase in score of cognitive variations was 6.74 in the memantine group and 3.62 in the placebo group with a nonsignificant difference (P = 0.125). The scores of each dimension of QoL in the two groups showed that in all four dimensions, the patient's physical, psychological, social, and environmental status increased significantly by time (P < 0.001).
Conclusions
According to the results of this study, memantine as an adjuvant to administration of sodium valproate may have a significant effect on decreasing the intensity of mania in the long run.
... [16] Similar to ketamine, other NMDA receptor antagonists have been shown to have antidepressant-like effects and to potentiate the effects of classical antidepressants in rodents. [17] Because ketamine and other NMDA antagonists have severe side effects and the potential for abuse, other glutamate-based approaches, including the potentiation of AMPA (alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, have increasingly become the focus of preclinical studies. The medical need for newer, better-tolerated and more efficacious treatments remains high. ...
... Unlike other NMDA receptor antagonists, memantine has neuroprotective properties that efficiently blocks excitotoxicity induced by hyperactivity of the NMDA receptors at therapeutically doses, thus restoring normal neurotransmission [22,35]. Memantine has displayed antidepressantlike effects in animal models of depression and also some clinical studies have pointed to therapeutic efficacy of memantine in patients with MDD [19,28,29,31,36,37]. However, the molecular mechanisms underlying the antidepressive properties of memantine in animal and clinical studies still have not been fully explored. ...
Background
Previous clinical and preclinical studies have indicated that the N-methyl-d-aspartate (NMDA) receptor antagonist, memantine, has neuroprotective properties as well as antidepressant effects. The present study was designed to examine behavioral and molecular effects of memantine administration in rats subjected to the repeated unpredictable stress (RUS) paradigm.
Methods
Rats were split into four groups at random including control + saline, control + memantine, stressed + saline and stressed + memantine. After 10 days of exposure to the RUS paradigm, rats were administered memantine (20 mg/kg) intraperitoneally (ip) for 14 days. Depression-like behavior and memory performance were assessed by measuring immobility time in the forced swim test and passive avoidance test, respectively. The mRNA levels of BDNF and TrkB in the prefrontal cortex and hippocampus were measured by real-time quantitative PCR.
Results
Our results demonstrated that the RUS paradigm caused depression-like behavior and impairment of memory retrieval in rats. We did not find significant changes in BDNF or TrkB mRNA levels in hippocampus, but mRNA levels of TrkB in the prefrontal cortex showed a significant downregulation. Administration of memantine reversed depression-like behavior and memory impairment and significantly increased BDNF and TrkB mRNA levels in both prefrontal cortex and hippocampus of stress exposed rats.
Conclusions
Our study supports the hypothesis that drugs with antagonistic properties on the NMDA receptor, such as memantine, might be efficient in treatment of major depression. Our results also suggest that upregulated mRNA levels of BDNF and TrkB in the brain might be essential for antidepressant-like activity of memantine in stress exposed rats.
... Memantine is a low-trapping, noncompetitive NMDA antagonist with antidepressant-like effects in preclinical models (Rogoz et al. 2002). In humans, a three-year, mirror-image, naturalistic study that added memantine to the treatment of 30 treatment-resistant patients with BD found that this agent substantially improved course of illness by preventing or ameliorating both depressive and manic episodes (Serra et al. 2015). ...
... In experimental studies the co-administration of fluoxetine and olanzapine was associated with positive effects in proteins involved with cell survival in the rat's brain [36; 52]. Fluoxetine in doses ineffective alone, when combined with different glutamatergic modulators, such as memantine, amantadine and neramexane increased antidepressant-like effects in rats subjected to the forced swimming test [53]. Interestingly, in the forced swimming test SSRI alone do not usually antidepressant-like effects [54]. ...
Background: Major depressive disorder (MDD) affects many people in the world. However, around 40% of patients do not respond to any pharmacological drugs. An alternative is to use a combination of different pharmacological groups or the combination of a classical antidepressant with a substance that can potentiate its effect. Purpose: Thus, this study aimed to investigate the synergistic interactions between different antidepressants, including fluoxetine, quetiapine and lamotrigine in combination with ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist. Methods: Wistar rats were acutely treated with fluoxetine (1.25 mg/kg), quetiapine (5 mg/kg), and lamotrigine (5.0 mg/kg) alone or in combination with ketamine (5.0 mg/kg), and then subjected to behavioral tests. In addition, oxidative damage and antioxidant capacity were assessed in the rat brain, and pro-inflammatory cytokines levels were evaluated in the serum. Results: It was observed a synergistic effect of ketamine in combination with fluoxetine on the immobility time in the forced swimming test, indicating an antidepressant effect. Other antidepressant did not show effects when administrated alone or joint to ketamine. The combination of ketamine with other antidepressants, particularly quetiapine, in some brain regions induced an increase in damage to lipids and proteins. However, the combination of ketamine with
fluoxetine increased the antioxidant activity of superoxide dismutase, and decreased oxidative damage, thus suggesting a neuroprotective effect of the combination of these drugs. The combination of ketamine with fluoxetine or lamotrigine reduced proinflammatory cytokines levels. Conclusion: In conclusion, ketamine induced antioxidant or pro-antioxidant effects dependent of antidepressant classes or brain area.
Keywords: Oxidative stress; antidepressants; ketamine; synergism; major depressive disorder
... Similarly, it was reported that patients who was suffering from major depressive disorders when treated with ketamine an antagonist of NMDA receptor, a significant antidepressant-like effect was accomplished [7,90]. Additionally, another approach in the search of discovery of antidepressant reported that standard antidepressant drugs have a synergistic effect with NMDA receptor antagonist in FST [70]. Antidepressant-like effects have been proved by several kinds of NMDA receptor antagonists in various animal models [13,42,44,64,66,83]. ...
Depression is one the world leading global burdens leading to various comorbidities. Lithium as a mainstay in the treatment of depression is still considered gold standard treatment. Similar to lithium another agent agmatine has also central protective role against depression. Since, both agmatine and lithium modulate various effects through interaction with NMDA receptor, therefore, in current study we aimed to investigate the synergistic antidepressant-like effect of agmatine with lithium in mouse force swimming test. Also to know whether if such effect is due to interaction with NMDA receptor. In our present study we found that when potent dose of lithium (30mg/kg) was administered, it significantly decreased the immobility time. Also, when subeffective dose of agmatine (0.01mg/kg) was coadministered with subeffective dose of lithium (3mg/kg), it potentiated the antidepressant-like effect of subeffective dose of lithium. For the involvement of NMDA receptor in such effect, we administered NMDA receptor antagonist MK-801 (0.05mg/kg) with a combination of subeffective dose of lithium (3mg/kg) and agmatine (0.001mg/kg). A significant antidepressant-like effect was observed. Furthermore, when subeffective dose (50 and 75mg/kg) of NMDA was given it inhibited the synergistic effect of agmatine (0.01mg/kg) with lithium (3mg/kg). Hence, our finding demonstrate that agmatine have synergistic effect with lithium which is mediated by NMDA receptor pathway.
... Memantine is a low-trapping, noncompetitive NMDA antagonist with antidepressant-like effects in preclinical models (Rogoz et al. 2002). In humans, a three-year, mirror-image, naturalistic study that added memantine to the treatment of 30 treatment-resistant patients with BD found that this agent substantially improved course of illness by preventing or ameliorating both depressive and manic episodes (Serra et al. 2015). ...
Currently available therapeutics for bipolar disorder (BD)—and bipolar depression in particular—are scarce and often ineffective. This is particularly troubling because the long-term course of bipolar depression comprises recurrent depressive episodes and persistent residual symptoms. Glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders, as well as in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the glutamatergic modulator ketamine were first observed, similar agents have been studied in both major depressive disorder (MDD) and BD. This chapter reviews the clinical and preclinical evidence supporting the use of novel glutamate receptor modulators for the treatment of bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics. The chapter discusses several specific agents, including N-acetyl cysteine (NAC), scopolamine, biperiden, agomelatine, riluzole, ketamine, memantine, creatine, metyrapone, ketoconazole, mifepristone, and celecoxib. Non-pharmacological somatic treatments are not reviewed.
... Memantine, another NMDA receptor blocker, however, do not display rapid antidepressant effect because it does not have any action on NMDA receptors at rest and therefore devoid of any affect on the downstream signaling process (elongation factor) and upregulation of BDNF [49]. Rogoz and colleagues have demonstrated that the memantine, when combined with traditional antidepressant agents, fluoxetine, imipramine and venlafaxine, showed synergistic antidepressant-like effect in the forced swim test [53]. Although memantine has displayed antidepressant-like effect in animal models [54,55], however, it failed to demonstrate the same in a double-blind placebo-controlled study [56]. ...
Introduction:
Treatment of patients suffering from major depression could be highly challenging for psychiatrists. Intractability as well as relapse is commonly seen among these patients, leading to functional impairment and poor quality of life. The present review discusses some of the novel investigational drugs that are under pre-clinical or clinical phases in the treatment of major depression. Areas covered: Molecules belonging to different classes such as triple reuptake inhibitors, opioid receptors, ionotropic and metabotropic glutamate receptors, and neurotrophin in the treatment of major depression are covered in this article. Expert opinion: Although the historical discovery of earlier antidepressant molecules (iproniazid and imipramine) is through serendipitous discovery, the present research focuses on discovering novel molecules based on our current pathophysiological knowledge of the disease condition. The fast-acting antidepressant property of N-methyl-d-aspartate (NMDA) receptor molecules, including ketamine is an exciting area of research. Other drug molecules such as amitifadine (triple reuptake inhibitor), ALKS-5461 (kappa receptor antagonist and mu opioidergic receptor agonist), rapastinel (NMDA glutamatergic receptor modulator) are under Phase-III clinical trials and could be approved in the near future for the treatment of major depression.
... Increasing of antidepressant-like activity of the NMDA receptor ligands by imipramine has been confirmed in preclinical studies. Use of this TCA together with, e.g., amantadine or memantine (Rogó _ z 2009;Rogó _ z et al. 2002Rogó _ z et al. , 2004, zinc (Cunha et al. 2008;Szewczyk et al. 2002Szewczyk et al. , 2009), L-701,324 and D-cycloserine ) enhanced the duration of animals' active behavior in the FST and TST (tail suspension test). Desipramine, tested in the present study, which belongs to the TCAs, is the active metabolite of imipramine and more strongly reduces the reuptake of noradrenaline (NA) than serotonin (5-HT) (Pu_ zynski 2005). ...
Pre-clinical and clinical studies indicated that a blockade of the NMDA receptor complex creates new opportunities for the treatment of affective disorders, including depression. The aim of the present study was to assess the influence of traxoprodil (10 mg/kg) on the activity of desipramine (10 mg/kg), paroxetine (0.5 mg/kg), milnacipran (1.25 mg/kg), and bupropion (10 mg/kg), each at sub-therapeutic doses. Moreover, brain levels of traxoprodil and tested agents were determined using HPLC. The obtained results were used to ascertain the nature of occurring interaction between traxoprodil and studied antidepressants. The experiment was carried out on naïve adult male Albino Swiss mice. Traxoprodil and other tested drugs were administered intraperitoneally. The influence of traxoprodil on the activity of selected antidepressants was evaluated in forced swim test (FST). Locomotor activity was estimated to exclude false positive/negative data. To assess the influence of traxoprodil on the concentration of used antidepressants, their levels were determined in murine brains using HPLC. Results indicated that traxoprodil potentiated activity of all antidepressants examined in FST and the observed effects were not due to the increase in locomotor activity. Only in the case of co-administration of traxoprodil and bupropion, increased bupropion concentrations in brain tissue were observed. All tested agents increased the traxoprodil levels in the brain. Administration of a sub-active dose of traxoprodil with antidepressants from different chemical groups, which act via enhancing monoaminergic transduction, caused the antidepressant-like effect in FST in mice. The interactions of traxoprodil with desipramine, paroxetine, milnacipran, and bupropion occur, at least partially, in the pharmacokinetic phase.
... NMDA application reversed the potent antidepressant like effect of DXM. This observed effect is consistent with ours and reports from other labs, where it is shown that NMDA receptor antagonists play a crucial role in antidepressant like effect of various drugs in FST and TST [39,41,[58][59][60][61]. ...
... Acute infusion of the NMDA receptor antagonist, ketamine, has been shown to have rapid antidepressant effects in treatment resistant patients (Berman et al, 2000;Zarate et al, 2006). Preclinical studies have also demonstrated rapid antidepressant-like effects of ketamine (Jett et al, 2015;Li et al, 2010;Rogóz et al, 2002). However, it is unlikely ketamine will ultimately be widely used as a therapeutic agent owing to its many substantial drawbacks, eg, psychotomimetic properties and abuse liability (Lodge and Mercier, 2015). ...
Deficits in cognitive flexibility are prominent in stress-related psychiatric disorders, including depression. Ketamine has rapid antidepressant efficacy, but it is unknown if ketamine improves cognitive symptoms. In rats, 2 weeks chronic intermittent cold (CIC) stress impairs reversal learning, a form of cognitive flexibility mediated by the orbitofrontal cortex (OFC) that we have used previously to model cognitive dysfunction in depression. We have shown that activating JAK2/STAT3 signaling in the OFC rescued the CIC stress-induced reversal learning deficit. Thus, in the present study we determined if ketamine also corrects the stress-induced reversal learning deficit, and if JAK2/STAT3 signaling is involved in this effect. A single injection of ketamine (10 mg/kg, i.p.), 24 h prior to testing rescued the CIC stress-induced reversal learning deficit. CIC stress decreased JAK2 phosphorylation in the OFC, and ketamine restored pJAK2 levels within 2 h post-injection. The JAK2 inhibitor, AG490, given systemically or into the OFC at the time of ketamine injection prevented its beneficial effect on reversal learning. We then tested the role of JAK2/STAT3 in ketamine-induced plasticity in the OFC. Ketamine depressed local field potentials evoked in the OFC by excitatory thalamic afferent stimulation, and this was prevented by JAK2 inhibition in the OFC. Further, in both the OFC and primary cortical neurons in culture, ketamine increased expression of the neural plasticity-related protein, Arc, and this was prevented by JAK2 inhibition. These results suggest that the JAK2/STAT3 signaling pathway is a novel mechanism by which ketamine exerts its therapeutic effects on stress-induced cognitive dysfunction in the OFC.Neuropsychopharmacology accepted article preview online, 17 October 2016. doi:10.1038/npp.2016.236.
... We showed that anti-depressant like effect of lamotrigine was boosted by using different types of NMDA receptor antagonists, supporting the implication of NMDA in antidepressant-like effect of lamotrigine. Our data are in consistent with other studies, demonstrating the antidepressant-like effect of NMDA receptor antagonists in FST [28,30,68]. ...
Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10 mg/kg) decreased the immobility time in the FST (P < 0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30 mg/kg) reduced the immobility time in the FST (P < 0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75 mg/kg), l-arginine (750 mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5 mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10 mg/kg) in the FST. Injection of l-nitroarginine methyl ester (l-NAME, 10 mg/kg, a non-specific NOS inhibitor), 7-nitroindazole (30 mg/kg, a neuronal NOS inhibitor), methylene blue (20 mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05 mg/kg), ketamine (1 mg/kg), and magnesium sulfate (10 mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5 mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis.
... Moreover, pre-clinical studies have shown that other agents, which act in neurotransmitter systems separatefrom the monoaminergic system, may enhance the effects of FLX. In fact, FLX when administrated alone was inactive; however, when FLX was combined with the uncompetitive N-methyl-Daspartate (NMDA) receptor antagonists, amantadine, memantine and neramexane, it showed positive effects in theanimal model of depression (Rogóz et al., 2002). So, the combination of traditional antidepressant drugs and other agents may produce enhanced antidepressant properties, and this is very important for antidepressant-resistant patients. ...
Dysfunction of the glutamate system has been associated with the pathophysiology of psychiatric disorders, including mood and anxiety disorders. Changes in levels and clearance of glutamate and its metabolites were found in cortical/limbic areas of depressed patients, while neuroimaging and histopathological studies showed morphological and functional alterations in the same brain areas. Preclinical studies on stress-based animal models of mood and anxiety disorders showed that stress potently affects glutamate synaptic transmission and plasticity and induces consistent dendritic remodeling and synaptic spines reduction in corresponding brain areas. Interestingly, chronic fluoxetine, as well as other traditional antidepressants, not only have been shown to modulate the glutamate system in basal conditions, but are also able to prevent the enhancement of glutamate release induced by acute stress and partly reverse the maladaptive changes in synapses and circuitry caused by exposure to chronic stress. Moreover, the chronic treatment with fluoxetine induces changes in the expression, regulation and function of glutamate receptors, reducing the activity of NMDA receptors, potentiating AMPA receptors, and modulating metabotropic glutamate receptors. These findings suggest that glutamate transmission may be a relevant target for the therapeutic action of antidepressants in general, and fluoxetine in particular. Understanding the action of traditional drugs on glutamate transmission could be of great help in developing new drugs directly targeted at the glutamate synapse.
... Moreover, those agents which antagonize the effects of NMDA receptor have been reported to have antidepressant activity [62,63]. Other researchers reported that drugs which attenuate or block the activity of NMDA receptor have mimicked the effects of antidepressants including lithium during FST [64][65][66]. It is worth to mention, that patient who shows resistant to antidepressant therapy, when undergoes ketamine therapy an NMDA antagonist, respond well and shows long lasting antidepressant effects [25,26]. ...
... Our results are in line with other studies which also showed that the drugs which block NMDA receptor have antidepressant like effects (Skolnick, 1999;Garcia et al., 2008;Paul and Skolnick, 2003). Moreover, many reports from the previous studies have shown that some antidepressant have a synergistic effect with NMDA receptor antagonists during FST (Ghasemi et al., 2009a(Ghasemi et al., , 2009bZomkowski et al., 2010;Rogóż et al., 2002). ...
... Recent studies indicate that ifenprodil co-administered with antidepressant agents with distinct pharmacological profiles, each given at ineffective doses, produced a significant antidepressant-like effect in the FST (Ghasemi et al. 2009;Poleszak et al. 2014). A similar effect on the duration of the immobility time was observed in animal studies in which low doses of other NMDA receptor antagonists were administered concomitantly with antidepressants in the following groups: TCAimipramine, SSRIfluoxetine, SNRIreboxetine, and a selective serotonin reuptake enhancer (SSRE)tianeptine (Maj et al. 1992a, b;Poleszak et al. 2011Poleszak et al. , 2013Poleszak et al. , 2014 (Pruus et al. 2010;Rogóż et al. 2002Rogóż et al. , 2004. ...
One of the newest substances, whose antidepressant activity was shown is traxoprodil, which is a selective antagonist of the NR2B subunit of the NMDA receptor. The main goal of the present study was to evaluate the effect of traxoprodil on animals' behavior using the forced swim test (FST), as well as the effect of traxoprodil (10 mg/kg) on the activity of antidepressants, such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg) and reboxetine (2.5 mg/kg). Serotonergic lesion and experiment using the selective agonists of serotonin receptors 5-HT1A and 5-HT2 was conducted to evaluate the role of the serotonergic system in the antidepressant action of traxoprodil. Brain concentrations of tested agents were determined using HPLC. The results showed that traxoprodil at a dose of 20 and 40 mg/kg exhibited antidepressant activity in the FST and it was not related to changes in animals' locomotor activity. Co-administration of traxoprodil with imipramine, fluoxetine or escitalopram, each in subtherapeutic doses, significantly affected the animals' behavior in the FST and, what is important, these changes were not due to the severity of locomotor activity. The observed effect of traxoprodil is only partially associated with serotonergic system and is independent of the effect on the 5-HT1A and 5-HT2 serotonin receptors. The results of an attempt to assess the nature of the interaction between traxoprodil and the tested drugs show that in the case of joint administration of traxoprodil and fluoxetine, imipramine or escitalopram, there were interactions in the pharmacokinetic phase.
... depressive disorders exhibited a significant anti-depressant effect [9]. Furthermore, it is also notable that antagonists at NMDA receptor display synergistic antidepressant-like property with standard antidepressants in the FST [10]. ...
In the current study, the involvement of N-methyl-D-aspartate receptor (NMDAR) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in the antidepressant-like effects of baclofen was evaluated by using animal model in forced swimming test. Followed by an open field test for the evaluation of locomotor activity, the immobility time for mice in force swimming test was recorded. Only the last four min was analyzed. Administration of Baclofen (0.5 and 1mg/kg, i.p.) reduced the immobility interval in the FST. Prior administration of l-arginine (750mg/kg, i.p.,) a nitric oxide synthase substrate or sildenafil (5mg/kg, i.p.) a phosphodiesterase 5 into mice suppressed the antidepressant-like activity of baclofen (1mg/kg, i.p.).Co-treatment of 7-nitroindazole (50mg/kg, i.p.,) an inhibitor of neuronal nitric oxide synthase, L-NAME (10mg/kg, i.p.,) a non-specific inhibitor of nitric oxide synthase or MK-801 (0.05mg/kg, i.p.) an NMDA receptor antagonist with subeffective dose of baclofen (0.1mg/kg, i.p.), reduced the immobility time in the FST as compared to the drugs when used alone. Co-administrated of lower doses of MK-801 (0.01mg/kg) or L-NAME (1mg/kg) failed to effect immobility time however, simultaneous administration of these two agents in same dose with subeffective dose of baclofen (0.1mg/kg, i.p.), minimized the immobility time in the FST. Thus, our results support the role of NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant-like action of baclofen.
Major Depressive Disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult-born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N-methyl-D-aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult-born GCs for antidepressant-like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B-containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)-(4-Hydroxyphenyl)-(βS)-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1μg each side) following a chronic fluoxetine (18 mg/kg/day) treatment - known to increase adult hippocampal neurogenesis - in a mouse model of anxiety/depression. Responses in a neurogenesis-dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and Gamma-aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid-acting antidepressant-like effect of local Ro25-6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine-independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.
Depressive disorder is the leading cause of disability worldwide, yet the mechanisms underlying depression are not fully understood. Vesicle release is essential for synaptic neurotransmission, the abnormalities of vesicle release and synaptic plasticity are associated with various neuropsychiatric disorders. Neural circuits are ensembles of interconnected neurons that collectively perform specific functions. To some extent, depression may be caused by a disruption in the structural and functional connections of the neural circuits underlying emotion regulation. In this review, we summarized the role of abnormalities of vesicle release and synaptic transmission, as well as the related regulatory molecules and signal pathways in the regulation of depression.
Major depression is a common, disabling, and often difficult-to-treat illness. Decades of research into the neurobiology and treatment of depression have greatly advanced our ability to manage this disorder. However, a number of challenges remain. A substantial number of depressed patients do not achieve full remission despite optimized treatment. For patients who do achieve resolution of symptoms, depression remains a highly recurrent illness, and repeated episodes are common. Finally, little is known about how depression might be prevented, especially in individuals at increased risk. In the face of these challenges, a number of exciting research efforts are currently under way and promise to greatly expand our knowledge of the etiology, pathophysiology, and treatment of depression. This review highlights these future prospects for depression research with a specific focus on lines of investigation likely to generate novel, more effective treatment options.
The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, β adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.
Aberrant depressive-like behaviors in olfactory bulbectomized (OBX) mice have been documented by previous studies. Here, we show that memantine enhances adult neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors via inhibition of the ATP-sensitive potassium (KATP) channel in OBX mice. Treatment with memantine (1–3 mg/kg; per os (p.o.)) for 14 days significantly improved depressive-like behaviors in OBX mice, as assessed using the tail-suspension and forced-swim tests. Treatment with memantine also increased the number of BrdU-positive neurons in the DG of OBX mice. In the immunoblot analysis, memantine significantly increased phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473), but not ERK (Thr-202/Tyr-204), in the DG of OBX mice. Furthermore, phosphorylation of GSK3β (Ser-9) and CREB (Ser-133), and BDNF protein expression levels increased in the DG of OBX mice, possibly accounting for the increased adult neurogenesis owing to Akt activation. In contrast, both the improvement of depressive-like behaviors and increase in BrdU-positive neurons in the DG following treatment with memantine were unapparent in OBX-treated Kir6.1 heterozygous (+/-) mice but not OBX-treated Kir6.2 heterozygous (+/-) mice. Furthermore, the increase in CaMKIV (Thr-196) and Akt (Ser-473) phosphorylation and BDNF protein expression levels was not observed in OBX-treated Kir6.1 +/- mice. Overall, our study shows that memantine improves OBX-induced depressive-like behaviors by increasing adult neurogenesis in the DG via Kir6.1 channel inhibition.
Introduction:
Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as "California Rocket Fuel" has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown.
Aim:
To analyze the effect of mirtazapine and venlafaxine alone or combined -given at doses with actions on the forced swim test- on female rat sexual behavior.
Methods:
Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (20/30, 10/15, 5/7.5 and 2.5/3.75 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity.
Results:
Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior.
Conclusions:
Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that "California Rocket Fuel" could be an effective antidepressant therapy with no adverse sexual effects in women.
Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice. Memantine (3 and 10 mg/kg, b.i.d.) was orally administered to ddY mice fed a TD diet for 22 days. During the treatment period, the forced swimming test, elevated plus-maze test, passive avoidance test, and locomotor activity test were performed. Neurotransmitter levels in the brain were analyzed after the treatment period. Daily oral administration of memantine ameliorated the memory disturbances, anxiety-like behavior, and depression-like behavior observed in TD mice. Memantine did not have a significant effect on monoamine levels, but increased glutamate levels in the hippocampus in TD mice. These results suggest that memantine prevents or suppresses the progression of BPSD-like behaviors that develop due to TD. This effect may be mediated in part by the enhancement of glutamatergic neuron activity in the hippocampus.
Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecularmechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neurosciencebased nomenclature that can incorporate such advances in drug development for TRD. This reviewaims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-termvulnerability to recurrent depressive episodes. © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
Depression is a nosological entity which may appear alone or concomitantly (e.g. in schizophrenia). Analysis of data from both clinical and experimental studies allows a conclusion that atypical antipsychotics, such as aripiprazole (ARI), may also be effective in treating depression in addition to antidepressants. The aim of the studies was to determine antidepressant efficacy of ARI, venlafaxine (VEN) and combined therapy using both drugs, in prenatally stressed rats (animal depression model) and control group. In addition, this article was aimed at determining the effect of these drugs on locomotor activity of these animals. The effect of chronic stress used in pregnant rats and the use of drugs such as ARI (1.5 mg/kg) and VEN (20 mg/kg) were studied in forced swimming test (FST; antidepressant effect) and locomotor activity test. Performed tests confirmed the antidepressant effect of ARI, VEN and efficacy of combined drugs in FST in both prenatally stressed rats (effect present upon single administration and after 7, 14 and 21 days of testing) and control group rats (effect present upon single administration and 7 days of testing). Moreover, upon single administration of the used drugs to prenatally stressed rats, it was found sedative effect – reduced animals’ locomotor activity. Study results have proven antidepressant and sedative efficacy of ARI, VEN and combined administration of these drugs. Due to the small amount of data on the above preparations, in particular in the context of animal depression models, further studies in this respect are recommended.
Time dependent sensitization (TDS) - phenomenon described originally by Chiodo and Antelman (1980) in context of dopamine receptors, refers to cascade of events that continue to develop in the organism, after the initiating stimulus is no longer available. Treatment could be recognized as such a initiating stimulus (in case of depression, example of electroconvulsive therapy would be obvious, but some aspects of pharmacotherapy too). The process leads to improvement, but, on the other hand, phenomena of kindling in recurrent depression is well known (more relapses and therapies make heavier and longer lasting subsequent episodes). Hence our interest in delayed effects of treatment. Here we report alterations in rat immune system after Imipramine (IMI) treatment cessation.
Wistar male rats were treated with IMI (10 mg/kg i.p. in 2 ml/kg of saline) repeatedly for 21 days or once - on the last day of drug administration period. Then the 3 weeks discontinuation phase begun, during which, at certain time points (3 h, 72 h, 7days, 21days) the trunk blood was collected. Tissue concentrations of IMI and its metabolite desipramine (DMI), as well as ACTH and various cytokines were measured.
The IMI and DMI was detectable only 3 h after the last i.p. injection of the drug. Ever since the second time point (72 h of discontinuation) the levels of either compound were below detection threshold.There was no significant changes in ACTH levels between rat groups, although IMI seemed to attenuate alterations of the hormone level comparing to control groups. We observed differences between groups regarding certain cytokines at certain time points. Namely: at 72 h of discontinuation IL-2 and IL-4 were elevated in sera of rats treated with IMI acutely; at 7d of discontinuation levels of IL-1α, IL-5, IL-10 and IL-12 were affected in both acutely and chronically treated animals.
Presented data support, regarding some cytokines in serum, the TDS theory. Furthermore they refer to important aspect of antidepressants (ADs) action – antidepressant discontinuation syndrome (ADS). The most frequently, ADS has been described in context of ADs-disrupted monoamine homeostasis. Here, the other principle (i.e. immunomodulation) of the syndrome is proposed.
Gabapentin as an anticonvulsant drug also has beneficial effects in treatment of depression. Previously we showed that acute administration of gabapentin produced an antidepressant-like effect in the mouse forced swimming test (FST) by a mechanism involves the inhibition of the nitric oxide (NO). Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (KATP), in the present study we investigated the involvement of KATP channels in antidepressant-like effect of gabapentin. Gabapentin at different doses (5-10 mg/kg) and fluoxetine (20 mg/kg) were administrated by intraperitoneal (ip) route, 60 and 30 min respectively before test. To clarify the probable involvement of KATP channels, mice were pretreated with KATP channel inhibitor or opener. Gabapentin at dose 10 mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20 mg/kg). Co-administration of sub-effective dose (1 mg/kg) of glibenclamide (inhibitor of KATP channels) with gabapentin (3 mg/kg) showed a synergistic antidepressant-like effect. Also, sub-effective dose of cromakalim (opener of KATP channels, 0.1 mg/kg) inhibited the antidepressant-like effect of gabapentin (10 mg/kg). None of the treatments had any impact on the locomotor movement. Our study for the first time revealed that antidepressant-like effect of gabapentin in mice is mediated by blocking the KATP channels.
Background and Aim: Despite the use of different drugs in the treatment of bipolar disorder, about 50 percent of the patients are not completely cured. To strengthen the treatment effect, various medications including new antiepileptic drugs and serotonin-dopamine antagonists have been studied. Considering the potential role of NMDA receptor antagonists on the mood changes, this study was conducted to investigate the effects of memantine on acute mania as an adjunctive therapy to lithium and risperidone. Material and Method: Our study was a double-blind randomized clinical trial which included 40 patients with bipolar disorder in the acute phase of mania. Patients in both groups were treated with the same drug regimen (including risperidone and lithium). In the intervention group, an oral dose of memantine, 5 mg/day was started and increased to 20 mg / day after 96 hours. Patients in the control group received placebo. Severity of the symptoms before starting treatment and at the 1st, 2nd, 4th and 6th weeks after treatment was measured based on the Young Mania Rating Scale. We estimated clinical side effects of memantine by using a clinical check list. Results: At the end of the study, severity of manic symptoms decreased in both groups, but speed and rate of reduction of the symptoms of mania were not significantly different in the memantine group compared with the placebo group (p=0.784). The most common side effects in both groups included; restlessness (p=1.000), tremor (p=0.501), and dizziness (p=0.605), which were not significantly different in both groups. Conclusion: Considering the limitations such as small sample size and short period of the study, addition of memantine 20 mg /day to the treatment regimen of the patients with bipolar disorder in the manic phase, for six weeks, had no effect on the rate and extent of symptoms of mania. © 2016, Kurdistan University of Medical Sciences. All rights reserved.
Aim:
To evaluate antidepressant-like effect of memantine in a rat model.
Methods:
Male Wistar rats were treated intraperitoneally with either vehicle, memantine (10 mg/kg) or imipramine (20 mg/kg), for 3 wk. Twenty-four hour after the last treatment animals were challenged with quinpirole (0.3 mg/kg s.c.) and tested for motor activity. After 1 h habituation to the motility cages, the motor response was recorded for the following 45-min and the data were collected in 5-min time bins.
Results:
As expected, chronic treatment with imipramine potentiated the locomotor stimulant effect of quinpirole. On the contrary, chronic memantine administration failed to induce the behavioral supersensitivity to the dopamine agonist.
Conclusion:
The results show that memantine, at variance with antidepressant treatments, fails to induce dopaminergic behavioral supersensitivity. This observation is consistent with the results of preclinical and clinical studies suggesting that memantine does not have an acute antidepressant action but does have an antimanic and mood-stabilizing effect.
N-Methyl-d-aspartate receptors (NMDARs) are broadly distributed in the central nervous system (CNS), where they mediate excitatory signaling. NMDAR-mediated neurotransmission (NMDARMN) is the molecular engine of learning, memory and cognition, which are the basis for high cortical function. NMDARMN is also critically involved in the development and plasticity of CNS. Due to its essential and critical role, either over- or under-activation of NMDARMN can contribute substantially to the development of CNS disorders. The involvement of NMDARMN has been demonstrated in a variety of CNS disorders, including schizophrenia, depression, posttraumatic stress disorder, aging, mild cognitive impairment and Alzheimer's dementia, amyotrophic lateral sclerosis, and anti-NMDAR encephalitis. Several targets to “correct” or “reset” the NMDARMN in these CNS disorders have been identified and confirmed. With analogy to aminergic treatments, these targets include the glycine/d-serine co-agonist site, channel ionophore, glycine transporter-1, and d-amino acid oxidase. It is still early days in terms of developing novel therapeutics targeting the NMDAR. However, agents modulating NMDARMN hold promise as the next generation of CNS therapeutics.
The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor N-G-nitro-L-arginine (L-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion L-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between L-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.
The majority of treatments for neuropsychiatric disorders have been based on serendipitous discoveries, with little understanding of the pathogenic and pathophysiological mechanisms underlying these disorders. As many of these disorders are sensitive to stress, an understanding of the physiology of stress is important in avoiding and reversing stress-sensitive disorders. Increased understanding of the glutamatergic synapse has revealed a system that is affected by both stress and multiple neuropsychiatric treatments, suggesting a possible convergent target in these disorders. This chapter reviews how traditional neuropsychiatric treatments affect the glutamatergic synapse, and how future therapies may be developed to more directly target this system.
Inescapable, but not escapable, stress inhibits the induction of Long Term Potentiation (LTP) in the CA1 region of hippocampus, a process that is dependent upon activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Since inescapable stress also produces a syndrome of behavioral depression sensitive to clinically effective antidepressants, we examined the actions of functional antagonists at the NMDA receptor complex in animal models commonly used to evaluate potential antidepressants. A competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid [AP-7]), a non-competitive NMDA antagonist (Dizolcipine [MK-801]), and a partial agonist at strychnine-insensitive glycine receptors (1-aminocylopropanecarboxylic acid [ACPC]) mimicked the effects of clinically effective antidepressants in these models. These findings indicate that the NMDA receptor complex may be involved in the behavioral deficits induced by inescapable stress, and that substances capable of reducing neurotransmission at the NMDA receptor complex may represent a new class of antidepressants. Based on these findings, the hypothesis that pathways subserved by the NMDA subtype of glutamate receptors are involved in the pathophysiology of affective disorders may have heuristic value.
Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.
Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The O-desmethyl compound Wy-45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal β-adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring-hydroxylated metabolite Wy-47,877 and the N-desmethyl metabolite Wy-45, 494 were also active in reserpine hypothermia, but Wy-45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy-45,233. None of the seven metabolites tested exhibited significated binding at dopamine-2, muscarinic cholinergic, α-1-adrenergic, histamine-1, or opiate (μ) receptors. These results suggest that Wy-45,233, the O-desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side-effect profile of venlafaxine.
This study demonstrated that distinct patterns of active behaviors are produced by antidepressants that selectively inhibit norepinephrine (NE) or serotonin (5-HT) uptake in the rat forced swimming test (FST). A behavior sampling technique was developed to score the active behaviors swimming, climbing and diving, as well as immobility. The rat's behavior was recorded at the end of each 5-s period during the test session. The sampling technique was both reliable, as demonstrated by test-retest reliability and inter-rater reliability, and valid, as shown by comparison to the timing of behavior durations. Five different antidepressant drugs which block monoamine uptake and two 5-HT1A receptor agonists were shown to decrease immobility in the FST; however, they produced distinct patterns of active behaviors. The selective NE uptake inhibitors desipramine and maprotiline selectively increased climbing, whereas the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline and paroxetine selectively increased swimming. The 5-HT1A receptor agonists 8-OH-DPAT and gepirone also selectively increased swimming. These results show that:1) SSRIs are not false negatives in the FST; 2) at least two behaviorally distinct processes occur in the FST; and 3) enhancement of NE neurotransmission may mediate climbing in the FST, whereas enhancement of 5-HT neurotransmission may mediate swimming.
Haloperidol (R 1625) is 50 to 100 times more active than chlorpromazine as an inhibitor of exploratory motor behaviour in rats. Emotional defaecation in rats is inhibited by both drugs at similar dose levels.
The present study characterized the in vitro NMDA receptor antagonistic properties of novel amino-alkyl-cyclohexane derivatives and compared these effects with their ability to block excitotoxicity in vitro and MES-induced convulsions in vivo. The 36 amino-alkyl-cyclohexanes tested displaced [3H]-(+)-MK-801 binding to rat cortical membranes with Kis between 1.5 and 143 μM. Current responses of cultured hippocampal neurones to NMDA were antagonized by the same compounds with a wide range of potencies (IC50s of 1.3–245 μM, at −70 mV) in a use- and strongly voltage-dependent manner (Δ 0.55–0.87). The offset kinetics of NMDA receptor blockade was correlated with equilibrium affinity (Corr Coeff. 0.87 P<0.0001). As an example, MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) had similar blocking kinetics to those previously reported for memantine (Kon 10.67±0.09×104 M−1 s−1, Koff 0.199±0.02 s−1, Kd=Koff/Kon=1.87 μM c.f. IC50 of 1.29 μM). Most amino-alkyl-cyclohexanes were protective against glutamate toxicity in cultured cortical neurones (e.g. MRZ 2/579 IC50 2.16±0.03 μM). Potencies in the three in vitro assays showed a relatively strong cross correlation (all corr. coeffs.>0.72, P<0.0001). MRZ 2/579 was also effective in protecting hippocampal slices against 7 min. hypoxia/hypoglycaemia-induced reduction of fEPSP amplitude in CA1 with an EC50 of 7.01±0.24 μM. MRZ 2/579 showed no selectivity between NMDA receptor subtypes expressed in Xenopus oocytes but was somewhat more potent than in patch clamp experiments-IC50s of 0.49±0.11, 0.56±0.01 μM, 0.42±0.04 and 0.49±0.06 μM on NR1a/2A /2B, /2C and 2/D, respectively. In contrast, memantine and amantadine were both 3-fold more potent at NR1a/2C and NR1a/2D than NR1a/2A receptors. All Merz amino-alkyl-cyclohexane derivatives inhibited MES-induced convulsions in mice with ED50s ranging from 3.6 to 130 mg/kg i.p. The in vivo and in vitro potencies correlated indicating similar access of most compounds to the CNS. MRZ 2/579 administered at 10 mg/kg resulted in peak plasma concentrations of 5.3 and 1.4 μM following i.v. and p.o. administration respectively, which then declined with a half life of around 170–210 min. Analysis of A.U.C. concentrations indicates a p.o./i.v. bioavailability ratio for MRZ 2/579 of 60%. MRZ 2/579 injected i.p. at a dose of 5 mg/kg resulted in peak brain extracellular fluid (ECF) concentrations of 0.78 μM (brain microdialysates). Of the compounds tested MRZ 2/579, 2/615, 2/632, 2/633, 2/639 and 2/640 had affinities, kinetics and voltage-dependency most similar to those of memantine and had good therapeutic indices against MES-induced convulsions. We predict that these amino-alkyl-cyclohexanes, which all had methyl substitutions at R1, R2, and R5, at least one methyl or ethyl at R3 or R4 and a charged amino-containing substitution at R6, could be useful therapeutics in a wide range of CNS disorders proposed to involve disturbances of glutamatergic transmission.
A new scoring technique is described that measures active behaviors of rats in the forced swimming test, a test that predicts antidepressant drug effects. The technique distinguishes the effects of selective serotonin reuptake inhibitors, which reduce immobility and increase swimming behavior, from selective norepinephrine reuptake inhibitors, which reduce immobility and increase climbing behavior. The magnitude of behavioral effects described for each drug (i.e., reduced immobility for both drugs, increased swimming for fluoxetine, increased climbing for desipramine) was greater when testing was conducted at the deeper 30-cm rather than the shallow 15-cm water depth. Results obtained with the technique demonstrate that selective serotonin reuptake inhibitors are not false negatives in the rat forced swimming test, as previously thought.
Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
The present study examined the effects of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test in rats and mice. Administered in a single dose or three times both examined compounds reduced the immobility time in rats. Active doses used in that test either did not change the locomotor activity or decreased it. A similar effect in both tests was shown by active (R)-enantiomers CGP 40116 and CGP 43487. Reduction of the immobility time induced by CGP 37849 and CGP 39551 in the forced swimming test in rats was antagonized by haloperidol and (+/-)-sulpiride, but not by SCH 23390 or prazosin. CGP 37849, but not CGP 39551, also reduced the immobility time in the forced swimming test in mice. The results obtained indicate that CGP 37849 and CGP 39551 induce an antidepressant-like effect in the forced swimming test, probably via an indirect dopamine activation resulting from blockade of NMDA receptors.
The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.
Recent studies from our laboratory have provided evidence that the 1-amino-adamantane derivative memantine (1-amino-3,5-dimethyl-adamantane) binds to the MK-801-binding site of the N-methyl-D-aspartate (NMDA)-receptor-gated ion channel. This action has been suggested to account for the antiparkinsonian and antispastic activity of the drug. In the present investigation we have extended our work by testing a series of 1-amino-adamantanes, including amantadine (1-amino-adamantane) and memantine, for their ability to compete with [3H]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a Ki-value of 0.19 +/- 0.06 microM while the weakest substance (1-N-methyl-amino-adamantane) had a Ki-value of 21.72 +/- 1.63 microM. The Ki-value of amantadine was 10.50 +/- 6.10 microM. In agreement with our earlier investigation, the Ki-value of memantine was 0.54 +/- 0.23 microM. The results indicate that 1-amino-adamantanes, in general, may produce their pharmacological effects through an interaction with the NMDA-receptor-gated ion channel. The displacement of [3H]MK-801 binding thus may provide the basis to predict the antiparkinsonian and antispastic activity of novel substituted 1-amino-adamantanes and possibly of other drugs.
The forced swimming test is reviewed. This test appears to be suitable for detecting antidepressant activity in rats but not in mice. Difference in experimental procedure may account for the different sensitivity to drugs of the two animal species.
In the mouse forced-swimming model, dose-dependent reversal of immobility was induced by the alpha-agonist clonidine given IP 30 min before testing. In addition, three preferential inhibitors of 5-HT uptake (citalopram, indalpine and fluvoxamine) had similar activity in the dose range 8-16 mg/kg as did the 5-HT1 agonist 8-OH-DPAT (1-4 mg/kg). Pretreatment with alpha-methyl-paratyrosine (100 mg/kg) did not prevent clonidine (1 mg/kg) action, suggesting that there was mediation by alpha post-junctional receptors. The effect of clonidine was unaltered by prazosin (2 mg/kg) and reversed by yohimbine (4 mg/kg) and 5-MeODMT (1 mg/kg), whereas it was potentiated by reserpine (2.5 mg/kg), methysergide (2 mg/kg) and ketanserin (8 mg/kg). Moreover, an ineffective dose of clonidine (0.06 mg/kg at 45 min pre-testing) made active subthreshold doses of various antidepressants (given at 30 min pre-testing): imipramine (4 mg/kg), amitriptyline (1 mg/kg), maprotiline (8 mg/kg), citalopram (2 mg/kg), indalpine, fluvoxamine and mianserin (4 mg/kg), viloxazine (2 mg/kg). Similar interactions were found with iprindole and nialamide (32 mg/kg), which were inactive alone up to 64 mg/kg, and 8-OH-DPAT (0.5 mg/kg) but not with major and minor tranquillizers. It is suggested that one effect of antidepressants might be the triggering of different relationships between alpha-2 and 5-HT mechanisms.
The novel bicyclic compound Wy-45,030 [1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol, hydrochloride] exhibited a neurochemical profile predictive of antidepressant activity. Like the tricyclic antidepressants, it inhibited rat brain imipramine receptor binding and synaptosomal monoamine uptake (dopamine as well as norepinephrine and serotonin). It did not inhibit monoamine oxidase. Unlike the tricyclic antidepressants, it was not antimuscarinic in the guinea pig ileum, nor did it have any appreciable affinity for brain alpha-1 adrenergic or histamine-1 binding sites. Wy-45,030 was also without affinity for alpha-2 or beta adrenergic, benzodiazepine, serotonin-1, serotonin-2, dopamine-2, and opiate receptors. Such a profile is predictive of antidepressant activity devoid of the side-effects common to tricyclic therapy.
Functional and biochemical experiments were performed with 1,3-dimethyl-5-aminoadamantan (D-145). The drug stimulates motor activity both in non-pretreated mice and in animals pretreated with reserpine and an inhibitor of tyrosine hydroxylase. It induces asymmetry in unilaterally striatotomized rats similar to amantadine and (+)-amphetamine but, in contrast to these drugs, the effect persists after pretreatment with reserpine and a tyrosine hydroxylase inhibitor. In contrast to amantadine and (+)-amphetamine, D-145 does not stimulate the flexor reflex activity of acutely spinalized rats. Biochemically, D-145 reduces central NA levels, but not DA levels and also induces to be released. It is concluded that D-145 activates DA receptors in the brain, both indirectly, i.e. via DA-release, and directly.
The pharmacological action of 1,3-dimethyl-5-aminoadamantane (D145), a new adamantane derivative, was studied in rats. It increased strongly the motor activity in normal and hypoactive (following reserpine, α-methyltyrosine or FLA-63 pretreatment) animals. Catalepsy induced by spiroperidol, haloperidol, fluphenazine and reserpine (but not by chlorpromazine) was antagonized; the flexor reflex in spinal rats was not affected. D145 had no significant effect on noradrenaline or dopamine brain levels. The body temperature was slightly raised. D145 did not antagonize the effect of oxotremorine. In contrast to amantadine, but like apomorphine, D145 evoked hypotension which was prevented by spiroperidol or haloperidol.It is concluded that D145 activates the central dopamine neurons. The compound under studies differs from amantadine and in many (but not in all) respects acts like apomorphine.
Inhibitor constants (Ki's) for blocking uptake of [3H]norepinephrine, [3H]serotonin, and [3H]dopamine into synaptosomal preparations of rat brain were determined for 25 antidepressants and putative antidepressants, some neuroleptics, stimulants, antihistamines and other monoamines. With Ki's we could directly and definitively compare the relative potencies of a drug at the three processes. Eighteen or 72% of the antidepressants (including tertiary amine tricyclics) were more potent at blocking uptake of norepinephrine than at blocking uptake of serotonin. Considering all three biogenic amines, 17 antidepressants were selective for blocking [3H]norepinephrine uptake, one (bupropion) was selective although weak for blocking [3H]dopamine uptake, and the remainder were selective for blocking [3H]serotonin uptake. The neuroleptics chlorpromazine and promazine were relatively potent at blocking uptake of [3H]norepinephrine and some tricyclic antidepressants (notably, trimipramine and butriptyline) were very weak at blocking any biogenic amine uptake.
The effect of manipulations aimed at modifying the function of the 5-HT system has been reviewed. 5-HT uptake inhibitors are devoid of any activity in rats and induce an anti-immobility effect in mice. The so-called 5-HT1A agonists reduce the immobility time with some differences in mice and rats, mice being less sensitive. None of the procedure aimed at reducing 5-HT function reduced immobility time. Therefore, the 5-HT system does not play a tonic role in animals performing the forced swimming test. The involvement of possible brain regions mediating the anti-immobility effects of 5-HT mimetic drugs has been discussed.
A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea‐pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5‐HT 3 and 5‐HT 4 receptors.
Clomipramine, paroxetine and fluoxetine inhibited [ ³ H]‐DAU 6215 binding to 5‐HT 3 recognition sites in NG 108‐15 cells with IC 50 values in the range 1.3–4 μ m . Litoxetine had an IC 50 of 0.3 μ m . The specific binding of [ ³ H]‐GR 113808 to 5‐HT 4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC 50 values ≥ 20 μ m ).
In whole ileal segments, concentration‐response curves to 5‐HT were biphasic, with the high‐ and low‐potency phases involving 5‐HT 4 and 5‐HT 3 receptors, respectively. Curves to 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: a 5‐HT 3 receptor agonist) and 5‐methoxytryptamine (5‐MeOT: a 5‐HT 4 receptor agonist) were monophasic. All antidepressants were used at concentrations lacking anticholinoceptor properties, as demonstrated in both electrically stimulated longitudinal muscle‐myenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 n m ).
Fluoxetine (0.1–1 μ m ) and litoxetine (0.3–3 μ m ) antagonized both the high‐ and low‐potency phases of the 5‐HT curve. Schild analysis for the low‐potency phase yielded pA 2 estimates of 6.6 ± 0.3 (Schild slope of 1.1) and of 6.6 ± 0.1 (Schild slope of 1.1), respectively. At higher concentrations (3 μ m ), fluoxetine markedly inhibited the 5‐HT response maximum. Clomipramine (10–300 n m ) inhibited, by a mechanism independent of concentration, both phases of the 5‐HT curve with a reduction of the maximum response. Paroxetine (1 μ m ) was ineffective on the high‐potency phase, but caused a rightward shift of the low‐potency phase (p K B : 6.1 ± 0.01).
Responses to 2‐methyl‐5‐HT were inhibited by 1 μ m fluoxetine (p K B : 5.4 ± 0.02). Like clomipramine (30 and 100 n m ), litoxetine (1 and 3 μ m ) produced rightward displacements of 2‐methyl‐5‐HT‐induced contractions, which were virtually independent of antidepressant concentration (p K B values: 6.0 ± 0.02 and 5.5 ± 0.01, respectively). At higher concentrations, fluoxetine (3 μ m ) and clomipramine (300 n m ) markedly reduced the 2‐methyl‐5‐HT response maximum. Paroxetine (1 μ m ) was ineffective.
Responses to 5‐MeOT were shifted to the right by fluoxetine (0.1–1 μ m ) and litoxetine (1 and 3 μ m ) in a concentration‐dependent manner. At higher concentrations, fluoxetine (3 μ m ) markedly reduced the 5‐MeOT response maximum, an effect also observed with 100 and 300 n m clomipramine. Paroxetine (1 μ m ) was ineffective.
In unstimulated LMMPs, the excitatory effects evoked by 5‐HT, 2‐methyl‐5‐HT and 5‐MeOT and the antagonism produced by 300 n m clomipramine were comparable to those obtained in whole ileal segments. This suggests that 5‐HT contained in the mucosa of whole preparations does not interfere with agonist‐induced contractile responses and with the inhibitory effect of antidepressant drugs.
In conclusion, our results show that clomipramine, fluoxetine, paroxetine and litoxetine possess low to moderate potency/affinity at both central and peripheral (enteric) 5‐HT 3 receptors. In contrast, all four antidepressants are virtually ineffective at central 5‐HT 4 receptors. Inhibition of 5‐HT 4 receptor‐mediated ileal contractions by fluoxetine, litoxetine and clomipramine may result from allosteric antagonism or, more likely, from post‐receptor blockade of second messenger generation. The interaction of antidepressants with central and peripheral 5‐HT 3 and 5‐HT 4 receptors may be relevant for both potential therapeutic action and adverse effects at gastrointestinal level.
The antidepressant properties of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the competitive NMDA receptor antagonist, CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentonoic acid) and its (R)-enantiomer CGP 40116, were studied in a chronic mild stress model of depression. In this model, animals subjected to a variety of mild stressors for a prolonged period of time show a substantial decrease in the consumption of palatable sucrose solution (anhedonia). It was previously demonstrated that the chronic mild stress-induced anhedonia can be reversed by chronic treatment with various antidepressant drugs. In this study we found that the stress-induced deficit in sucrose intake was gradually reversed by chronic (4-5 weeks) treatment with MK-801 (0.3 mg/kg i.p.), CGP 37849 (5 mg/kg i.p.) and CGP (25 mg/kg p.o.). The magnitude of this effect and its time course were comparable to those observed following similar administration of imipramine (10 mg/kg i.p. or p.o.). The increase in sucrose intake following chronic administration of imipramine and NMDA receptor antagonists was specific to stressed animals; the behaviour of non-stressed controls was unchanged by any of the drugs tested. These results confirm those of previous studies, carried out on 'normal' animals, suggesting that antagonists of NMDA receptors may have antidepressant properties.
In the mouse forced swimming test (FST) pretreatment with a subactive dose of lithium (1 mEq/kg), given IP 45 min before the test, facilitated the antidepressant activity of iprindole, fluoxetine, and moclobemide (given IP 30 min before the test). These antidepressants (ADS) were not active alone in the FST in this study. Moreover, when subactive lithium was combined with a wide range of ADS, each given at subactive doses, those ADS with serotoninergic properties (e.g. imipramine, citalopram, paroxetine, fluoxetine, trazodone, mianserin, and moclobemide) significantly reduced immobility times. ADS acting primarily on noradrenaline (NA) or dopamine (DA) systems (desipramine, maprotiline, viloxazine, and bupropion) did not significantly decrease immobility when given in combination with lithium. This was also the case for RO 16 6491 [a reversible, B specific monoamine oxidase inhibitor (MAOI)], nialamide, and pargyline (both irreversible, mixed MAOIs). The anti-immobility effect of iprindole in combination with lithium suggests either a direct or indirect action on the serotonin (5HT) system by this ADS whose mechanism of action remains obscure. These results, using an animal behavioral model of depression and combining our present knowledge of the acute action of various ADS, support the hypothesis that the potentiation by lithium of ADS is via direct 5HT mechanisms, indirectly via a NA/5HT link, and/or by second messenger systems. Lithium may also facilitate the expression of antidepressant activity of ADS not active by themselves in the FST.
Central effects of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, were studied in male Albino-Swiss mice. CGP 37849--at high doses only--increased the locomotor activity, while CGP 39551 decreased it. CGP 37849 and CGP 39551 did not change the locomotor activity, in monoamine-depleted mice (treated with reserpine + alpha-methyltyrosine). However, when administered together with clonidine, both those compounds produced a distinct hyperactivity. That antiakinetic effect was antagonized by haloperidol, but not by prazosin or idazoxan. In monoamine-depleted mice both the CGP compounds inhibited the locomotor hyperactivity evoked by apomorphine or L-DOPA (given jointly with benserazide). CGP 37849 antagonized the catalepsy evoked by fluphenazine, haloperidol, spiperone and reserpine. After CGP 39551 administration, a decreased muscle tension was observed, which rendered evaluation of the influence on catalepsy impossible. The obtained results (the antiakinetic effect, antagonized by haloperidol, and the anticataleptic effect) indicate that the NMDA receptor antagonists studied may act via an indirect activation of the dopamine system.
The 1-aminoadamantanes memantine (1-amino-3,5-dimethyl-adamantane) and amantadine (1-amino-adamantane) are clinically used as anti-parkinsonian, anti-spasticity, anti-dementia and antiviral drugs. In the present investigation we have tested a series of 1-aminoadamantane derivatives including memantine and amantadine for their ability to compete with [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. The Ki values ranged from 0.237 +/- 0.019 microM for 1-N-dimethyl-amino-3,5-dimethyl-adamantane to 20.25 +/- 16.48 microM for amantadine. The Ki value of memantine was 19.98 +/- 3.08 microM and was thus very similar to that of amantadine. Memantine, at therapeutic concentrations, probably does not interact with the sigma binding site. Amantadine, at therapeutic concentrations, probably binds both to the sigma site and to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor.
The effects of amantadine, its dimethyl derivative, memantine and the chemically unrelated compound bifemelane were tested for antidepressant activity. Reserpine-induced hypothermia and the forced swim test (Porsolt test) were selected for this purpose. In the former test amantadine and bifemelane but not memantine were effective. In the forced swim test all three agents produced antidepressive-like activity (decreased immobility time), but in case of bifemelane it was less pronounced. The effect in the forced swim test was specific i.e. it was apparently not the result of an increase in general activity as evidenced by control experiments in the open field. The mechanism of amantadine and memantine action may involve indirect dopaminomimetic activity resulting from the blockade of NMDA receptors. However in reserpine-induced hypothermia this explanation is not valid considering the lack of effect of memantine and positive action of amantadine. Hence, amantadine may have an additional central sympathomimetic action that memantine is lacking. Bifemelane antidepressant-like activity might be attributed to an enhancement of noradrenergic transmission. We suggested that amantadine and bifemelane could be particularly useful therapeutically when depressive symptoms are present in patients suffering from Parkinson's disease and dementia.
The disorders discussed in this article share common problems with treatment-resistant depression both in research and clinical treatment. Lack of clear treatment-resistant definitions leads to difficulties in comparing the results of research studies. The absence of double-blind, placebo-controlled studies that match alternative treatments against each other creates confusion for the clinician who has to decide on a treatment paradigm. The future will, no doubt, see an increase in interest in treatment-resistant research and the answer to some of these questions. Although this review emphasizes the work that remains to be done before treatment resistance becomes a curiosity of the past, it also highlights the wealth of treatment options available to clinicians and their patients. As long as treatment-resistant patients are amendable to trying new therapies, hope that their depressions will lift remains.
We determined the uptake blockade produced by eight new antidepressant drugs (etoperidone, femoxetine, lofepramine, nefazodone, paroxetine, sertraline, tomoxetine, and venlafaxine), two metabolites of newer antidepressants (desmethylsertraline and norfluoxetine), seven previously reported antidepressants, and carbamazepine. Inhibitor constants (Kis) for uptake blockade were obtained from competitive uptake studies with [3H]norepinephrine, [3H]5-hydroxytryptamine, and [3H]dopamine in rat brain synaptosomes prepared from hippocampus, frontal cortex, and striatum, respectively. Among the newer compounds, tomoxetine (Ki = 0.7 nM) and lofepramine (Ki = 1.9 nM) were potent and selective [3H]norepinephrine uptake blockers; paroxetine (Ki = 0.73 nM), sertraline (Ki = 3.4 nM), and femoxetine (Ki = 22 nM) potently and selectively inhibited [3H]5-hydroxytryptamine uptake. Although none of the drugs was potent for [3H]dopamine uptake blockade, sertraline was the most potent (Ki = 260 nM). These data are useful in predicting adverse effects and drug-drug interactions of antidepressants.
The immobility time in the mouse forced swimming test was dose-dependently reduced by sigma 1 receptor agonists, such as 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) and (+)-pentazocine, and non-specific sigma receptor agonists, such as 1,3-di(2-tolyl)guanidine (DTG) and (+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylamin e hydrochloride (JO-1784). On the other hand, pre-treatment with N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma 1 receptor antagonist, completely antagonized the SA4503-, (+)-pentazocine- and DTG-induced reductions in immobility time. Such phenomena indicate that sigma receptor agonists alleviate behavioral despair. In addition, these antidepressive effects involve mainly the sigma 1 receptor subtype.
Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.
Involvement of 5-hydroxytryptamine (5-HT)3 receptors in action of antidepressants was examined in the forced swim test in rats. Rats were forced to swim in a cylinder for 15 min on day 1 and for 5 min on day 2. Imipramine, desipramine and mianserin, administered after the 15-min swim session on day 1 and before the 5-min swim test on day 2, dose-dependently decreased the duration of immobility in the swim test on day 2. 1-(m-Chlorophenyl)-biguanide (mCPBG) attenuated the decreased duration of immobility induced by imipramine, desipramine and mianserin, although mCPBG did not affect the duration of immobility when it was given alone. ICS205-930 dose-dependently decreased the duration of immobility in the swim test on day 2, and the effect of ICS205-930 was attenuated by mCPBG. These results suggest that the suppression of 5-HT3 receptor activity may contribute to the action of antidepressants.
Our ability to treat depression has improved with the availability of receptor-specific and chemically diverse groups of antidepressants. Even now, most of the short-term studies indicate that about 20% of depressed patients remain resistant to treatment. Therefore, it is important to properly assess the treatment-resistant depressed (TRD) patients and to separate the truly refractory patients from those inadequately treated. Undiagnosed medical conditions should be eliminated. TRD is neither a clinically nor a biologically identifiable entity. As there are no established methods for the treatment of TRD, all options should be considered. The clinician can be enriched by the knowledge of the treatment modalities available, and yet, in treating an individual patient, clinical skills, intuitive judgment, family history of response to drugs and side effects, all play a vital role. Several of the approaches described in the paper indicate available methods and their merits in general but there is no way of ascertaining by which particular method a patient should be treated. The three common methods of treatment are substitution of one antidepressant drug for another, combination therapies and augmentation techniques. These are based on clinical experiences and not research findings. Therefore the treatment of TRD patients is more an art than a science. The physician should assess all the psychopathological, phenomenological and psychosocial variables to appropriately treat an individual patient.
A wide variety of definitions are used for Treatment Resistant Depression (TRD), considering various criteria and different concepts. Some of the key issues are: the diagnosis, the treatment adequacy in terms of dose and duration, the treatment response assessment and the number of failed therapeutic trials required. Systematic research has been characterizing the concept and criteria to define the different variables involved. Lack of consensus on these issues limits comparison across clinical trials and interpretation of treatment efficacy in the management of treatment resistant patients. Through reanalyzes of available data, we point out the limits of TRD definitions and propose conceptual and operational criteria for a collaborative research project on TRD. It appears that a number of variables commonly associated to treatment resistance are independent of patients characteristics and mainly refer to misdiagnosis and inadequate treatment. The proposed criteria are intended for therapeutic trials in TRD, combining the evaluation of treatment efficiency and the validation of the concept of TRD itself. Major depression with poor response to two adequate trials of different classes of antidepressants is proposed for an operational definition of TRD. Rationale for this definition is discussed in contrast to alternative definitions.
Amantadine, originally used in the treatment and prophylaxis of influenza infection, has also proved beneficial in drug-induced Parkinsonism, Parkinson's disease, traumatic head injury, dementia, multiple sclerosis and cocaine withdrawal. Amantadine appears to act through several pharmacological mechanisms, none of which has been identified as the one chief mode of action. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels. However, it is still uncertain which of these actions are relevant in therapeutic doses. One new aspect is the antiviral effect of amantadine on Borna disease virus, which it is suspected may possibly play a role in affective disorders. All of these actions could constitute an antidepressant property, and it is suggested that amantadine might work as an antidepressant not through one, but through several mechanisms thought to be related to antidepressant activity. Effects of amantadine on symptoms of affective disorders have been demonstrated in several trials administering it for varying purposes. Additionally, animal studies as well as clinical trials in humans have hinted at an antidepressant activity of amantadine. We present here an overview of the current data. However, only a limited body of evidence is available, and further studies are needed to investigate the efficacy of amantadine as well as its modes of action in depression.
Despite a remarkable structural diversity, most conventional antidepressants may be viewed as 'monoamine based', increasing the synaptic availability of serotonin, norepinephrine, and/or dopamine. Both preclinical and recent clinical studies indicate that compounds which reduce transmission at N-methyl-D-aspartate (NMDA) receptors are antidepressant. Moreover, chronic administration of antidepressants to mice alters both the mRNA levels encoding N-methyl-D-aspartate receptor subunits and radioligand binding to these receptors within circumscribed areas of the central nervous system. It is hypothesized that these two different treatment strategies converge to produce an identical functional endpoint: a region-specific dampening of NMDA receptor function. The pathways leading to this convergence provide a rudimentary framework for discovering novel antidepressants.
N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson's disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine's moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine.
A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression.
Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions.
Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment).
These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.
The authors studied the effect of sertraline, one of selective serotonin reuptake inhibitors (SSRIs), and pramipexole, administered jointly, to male Wistar rats in the forced swimming test. Both those drugs were injected three times (24, 5 and 1 h before the test): sertraline at doses of 5 and 10 mg/kg ip, pramipexole at doses of 0.05, 0.1 and 0.3 mg/kg sc. Sertraline given separately was inactive in the test used. Pramipexole reduced the immobility time only at a dose of 0.3 mg/kg. Joint administation of both those drugs distinctly shorted the immobility time, that effect.being particularly strong at pramipexole, 0.3 mg/kg, and sertraline, 5 or 10 mg/kg. The obtained results indicate that sertraline--like the previously tested citalopram and fluoxetine--shows a synergistic effect when given with pramipexole in the forced swimming test.
The obtained results indicate that joint administration of amantadine (a non-competitive NMDA receptor antagonist) and imipramine induced antidepressant-like effect in the forced swimming test even at doses of both drugs which were ineffective when each of the drugs was used alone.
The type 3 serotonin (5-HT(3)) receptor is a ligand-gated ion channel. In concentration-clamp experiments, we investigated the effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists memantine, amantadine and MRZ 2/579 on 5-HT receptors stabley expressed in HEK-293 cells and on native 5-HT(3) receptors in the N1E-115 cell line. All agents antagonized serotonin (10 microM)-induced inward currents with similar potency to that reported for NMDA receptors. This effect was characterized by inducing a pronounced receptor desensitization, and was probably non-competitive and voltage-independent. In contrast, (S)-ketamine was much weaker as an antagonist of 5-HT(3) receptors than NMDA receptors. Similar effects on 5-HT(3) receptors have been reported previously for a variety of anti-depressants and it is possible that the clinical anti-depressant effects reported for both memantine and amantadine are mediated, at least in part, by antagonistic effects at 5-HT(3) receptors.
The aim of the present study was to examine SA4503 [1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a novel selective receptor agonist, in respect of its potential antidepressant action. To this end we used a forced swimming test in rats to study SA4503 alone, as well as its interaction with imipramine, a classic tricyclic antidepressant. SA4503 decreased the immobility time in the forced swimming test in rats (although only at one of the three doses used); at the same time it did not change the locomotor activity recorded under the same experimental conditions. Moreover, SA4503 showed a synergistic effect with imipramine in the forced swimming test (both those compounds given jointly decreased the immobility time, but were ineffective when administered separately). It had previously been shown that repeated administration of antidepressants with different pharmacological profiles enhanced the action of D-amphetamine, quinpirole and other dopamine stimulants. SA4503 administered repeatedly increased the locomotor hyperactivity induced by D-amphetamine and quinpirole (a dopamine D /D receptor agonist), but not by (+/-)-7-hydroxy-dipropyloamino-tetralin hydrobromide [(+/-)-7-OH-DPAT; a dopamine D receptor agonist]. The results presented in this paper support the suggestion that SA4503 may have potential antidepressive properties.
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Affinities of 5-HT uptake inhibitors for 5-HT3 receptors in both binding and functional studies
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Behavioral despair in rats, a new model sensitive to antidepressant treatments
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