Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice.

BACKGROUND: Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice. METHODS: A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. METHODS: A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. CONCLUSION: Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.

The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC.

(S)-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have indicated that the combined administration of (R)-ketamine and the mGlu2/3 receptor antagonist LY341495 (mixRL) induces rapid and sustained effects in the chronic unpredictable mild stress (CUMS) model of depression in mice, and the use of this drug combination is associated with a low risk of undesirable effects. Considering the possible influence of stress on cortical plasticity and, on the other hand, the role of this plasticity in the mechanism of action of ketamine, we decided to investigate whether mixed RL affects synaptic plasticity in the prefrontal cortex (PFC) in the CUMS model of depression using electrophysiological techniques and explore whether these effects are related to memory impairments. Using behavioral methods, we found that a single administration of mixRL reversed CUMS-induced PFC-dependent memory deficits and alleviated depression-like effects induced by CUMS. In turn, electrophysiological experiments indicated that the amplitude of field potentials as well as paired-pulse responses in CUMS mice were increased, and mixRL was found to reverse these effects. Additionally, the magnitude of long-term potentiation (LTP) was reduced in CUMS mice, and mixRL was shown to restore this parameter. In summary, mixRL appeared to exert its antidepressant effects and cognitive enhancing effects in a mouse model of depression, at least in part, by mechanisms involving modulation of glutamatergic transmission and LTP in the PFC.

The role of mGlu2/3 receptor antagonists in the enhancement of the antidepressant-like effect of ketamine.

MGlu2/3 receptor antagonists produce antidepressant-like effects in animal models of depression. A number of mechanisms responsible for these actions are convergent to the mechanism of the fast antidepressant-like effect of ketamine. Furthermore, the data indicate that ketamine effect is related to the action of mGlu2 receptors and may be reduced by their agonists. The above facts became the basis for the hypothesis that the antidepressant effect of low doses of ketamine might be enhanced by coadministration of a mGlu2 receptor antagonist. This strategy was aimed not only at enhancing the therapeutic effect of ketamine but also at reducing the risk of undesirable effects by lowering its therapeutic dose. It is known that ketamine, effective in relieving depressive symptoms in patients suffering from treatment-resistant depression (TRD), is burdened with a number of side effects, which may be particularly dangerous in psychiatric patients. Data have confirmed that subeffective doses of ketamine and its enantiomer, (R)-ketamine, coadministered with an mGlu2/3 receptor antagonist, induce antidepressant-like effects in the screening tests and in the chronic-stress-induced model of depression. At the same time, these drug combinations did not cause undesirable effects characteristic of higher doses of ketamine and (S)-ketamine, including those related to psychostimulatory effects. Further research is required to prove whether this strategy will also be effective in depressive patients.

Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism.

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.

The effectiveness of (R)-ketamine and its mechanism of action differ from those of (S)-ketamine in a chronic unpredictable mild stress model of depression in C57BL/6J mice.

(S)-ketamine has been approved as a rapid-acting antidepressant drug (RAAD). Although ketamine has an advantage over classic antidepressants (ADs) due to its rapid action, it remains a controversial drug due to its undesirable effects. Behavioral studies indicate that another enantiomer of ketamine, namely, (R)-ketamine, has been proposed as a safer but still effective RAAD. However, these conclusions have not been confirmed in any model of depression based on chronic environmental stress, which effectively reflects the core symptoms of this disease. Thus, we decided to compare the effects of (R)- and (S)-ketamine on chronic unpredictable mild stress (CUMS) in mice. Behavioral studies showed that (R)-ketamine induced anti-anhedonic and anti-apathetic efficacy up to seven days after administration, while the (S)-ketamine effect persisted up to 24 h or 3 days after injection. The behavioral effects of (R)-ketamine depended on the activation of TrkB receptors, while the (S)-ketamine effects did not. Western blot analyses showed that (S)-ketamine action might be related to both mTOR and ERK pathway activation and to the increased expression of GluA1 protein in the prefrontal cortex (PFC). In contrast, (R)-ketamine did not change ERK phosphorylation in the PFC, while it increased mTOR expression. (S)-Ketamine produced behavioral effects indicative of possible side effects in the dose range studied, while (R)-ketamine did not. This indicates that (R)-ketamine may be more effective, have a longer-lasting effect, and be safer to use than (S)-ketamine.

The group II mGlu receptor antagonist LY341495 induces a rapid antidepressant-like effect and enhances the effect of ketamine in the chronic unpredictable mild stress model of depression in C57BL/6J mice.

Ketamine produces a rapid antidepressant effect, but its use can be associated with serious side effects. Hence, other therapeutic options that will allow us to obtain a quick and safe antidepressant effect by modulating glutamatergic transmission are needed. Antagonists of mGlu2/3 receptors, which share some mechanisms of action with ketamine, may be good candidates to obtain this effect. Here, we show that the metabotropic glutamate (mGlu) 2/3 receptor antagonist LY341495 induced a dose-dependent antidepressant-like effect in the chronic unpredictable mild stress (CUMS) model of depression in C57BL/6J mice after both single and subchronic (three-day) administration. Furthermore, a noneffective dose of LY341495 (0.3 mg/kg) given jointly with a noneffective dose of ketamine (3 mg/kg) reversed the CUMS-induced behavioral effects, indicating that coadministration of ketamine with an mGlu2/3 receptor antagonist might allow its therapeutically effective dose to be lowered. Western blot results indicate that mTOR pathway activation might be involved in the mechanism of action of this drug combination. Moreover, the combined doses of both substances did not produce undesirable behavioral effects characteristic of a higher dose of ketamine (10 mg/kg) commonly used in rodent studies to induce antidepressant effects. Coadministration of low doses of ketamine and LY341495 did not induce the hyperactivity typical of NMDA channel blockers, did not disturb short-term memory in the novel object recognition (NOR) test, and did not disturb motor coordination in the rotarod test. Our research not only confirmed the earlier data on the rapid antidepressant effect of mGlu2/3 receptor antagonists but also indicated that such compounds can safely lower the effective dose of ketamine.

The influence of the duration of chronic unpredictable mild stress on the behavioural responses of C57BL/6J mice.

The chronic unpredictable mild stress (CUMS) model of depression in mice is a model commonly used to investigate stress-induced depressive-like behaviours. The duration of the stress-inducing procedure is variable, thus making it difficult to compare results and draw general conclusions from different protocols. Here, we decided to investigate how the duration of the CUMS procedure affects behavioural changes, body weight as well as the level of plasma corticosterone in stressed and nonstressed C57BL/6J mice subjected to CUMS for 18 or 36 days. We found that 18 days of CUMS induced a robust decrease in grooming time in the splash test and a significant increase in the immobility time in the tail suspension test (TST) and the forced swim test (FST). All of these stress-induced depression-related behavioural effects diminished or even disappeared after 36 days of CUMS. Plasma corticosterone levels were increased in the CUMS mice compared to those in the nonstressed mice. However, this effect was more pronounced in mice stressed for 18 days. On the other hand, a gradual decline in weight loss in the stressed animals was observed as the duration of the CUMS procedure increased. Altogether, the results indicate that 18 days of CUMS did not affect body weight but caused significant behavioural effects as well as a robust increase in corticosterone levels, while 36 days of CUMS induced significant reduction in weight gain but only slight or even non-significant behavioural effects. These results may indicate the presence of adaptive changes to the long-term CUMS procedure in C57BL/6J mice.

Role of AMPA receptor stimulation and TrkB signaling in the antidepressant-like effect of ketamine co-administered with a group II mGlu receptor antagonist, LY341495, in the forced swim test in rats.

Ketamine has been shown to induce a rapid antidepressant effect on patients with depression. In many animal models, both rapid and sustained antidepressant activities were also found in response to an antagonist of group II metabotropic glutamate receptors, LY341495, and its mechanism of action seemed to be similar in many ways to the action of ketamine. It has also been found that LY341495 enhanced the antidepressant-like activity of sub-effective doses of ketamine in rats without inducing adverse effects. Here, we investigated the role of AMPA receptor and TrkB receptor activation in the antidepressant-like effects of ketamine (3 mg/kg) co-administered with LY341495 (0.1 mg/kg), in the forced swim test in rats, at three time points (40 min, 3 h and 24 h) after joint administration of the tested compounds. It was found that the AMPA receptor antagonist NBQX (10 mg/kg) reversed the antidepressant effect of ketamine co-administered with LY341495 at all tested time points, whereas the TrkB receptor antagonist ANA-12 contributed to blockade of the effect of ketamine and LY341495 3 h after their joint administration. These results indicate that activation of AMPA receptor and BDNF-related signaling may play a role in the mechanism of antidepressant action of ketamine co-administered with LY341495.

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs.

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25-0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

The role of glutamatergic modulation in the mechanism of action of ketamine, a prototype rapid-acting antidepressant drug.

Over the past decade, ketamine has been one of the most commonly studied potential antidepressants. This is because it produces a spectacularly rapid and persistent therapeutic effect in people suffering from severe treatment-resistant depression (TRD), for which classical drugs are ineffective. Similar efficacy was demonstrated for scopolamine, a drug belonging to a completely different pharmacological group. This interesting coincidence piqued the interest of psychopharmacologists and prompted them to search for a possible common mechanism of these rapid acting antidepressant drugs (RAADs). A thorough explanation of this mechanism is also important because each of these substances induces serious side effects. Knowing the mechanism responsible for the therapeutic efficacy of RAADs could lead to minimizing, or even avoiding certain undesirable effects. This review provides an overview of the mechanism of action of a prototype RAAD, ketamine, in animal models, with a particular focus on the roles of NMDA receptors, AMPA receptors, synaptogenesis, and modulation of glutamate transmission by other modulators of this system, such as mGlu receptor ligands. Recently studied roles for ketamine enantiomers and metabolites in its rapid antidepressant effect are also considered. Finally, the results of multiple clinical trials are reported and discussed in relation to basic research. This review concludes that success in introducing novel therapeutic RAADs will depend on better cooperation and integration of neuroscience research and clinical practice.

The potential antidepressant action and adverse effects profile of scopolamine co-administered with the mGlu7 receptor allosteric agonist AMN082 in mice.

Scopolamine, a muscarinic cholinergic receptor antagonist, exerts fast and prolonged antidepressant effects in the clinic. In contrast, the current treatments for major depressive disorder (MDD) require long-term drug administration. On the other hand, the sole use of scopolamine might be related to the high risk of adverse effects. Therefore, it may be preferable to reduce its therapeutic dose. A new approach might include the co-administration of low-dose scopolamine with selected ligands of metabotropic glutamate (mGlu) receptors, which are known to possess antidepressant-like activity in several rodent tests and models of depression. The aim of the present study was to evaluate the potential antidepressant activity of low-dose scopolamine combined with an allosteric agonist of mGlu7 receptors, AMN082 in C57BL/6 mice. It was found that the combination of scopolamine (0.1 mg/kg) and AMN082 (1 mg/kg) exerted significant antidepressant-like effects in the tail suspension test (TST), but these effects were not observed in the mGlu7-/- mice. Furthermore, low-dose AMN082 co-administered with low-doses scopolamine (0.03 and 0.1 mg/kg) induced antidepressant-like activity in the forced swim test (FST) in mice. The tested compounds did not affect locomotor activity and did not impair spatial memory in the Morris water maze (MWM) test or motor coordination in the rotarod test. The results strongly indicated that there is an enhanced antidepressant-like action of scopolamine by AMN082. Co-administration of scopolamine with AMN082 might be a new strategy with better efficacy and a lower risk of adverse effects compared with the sole use of scopolamine or AMN082.

The involvement of monoaminergic neurotransmission in the antidepressant-like action of scopolamine in the tail suspension test.

Some clinical studies indicate that scopolamine may induce a rapid antidepressant effect. Although scopolamine is a muscarinic antagonist, it seems that not only cholinergic but also glutamatergic and GABAergic systems might be involved in the mechanism of its antidepressant activity in animal models of depression. Here, we present a set of behavioral data aimed at investigating the role of monoaminergic system activity in the mechanism of the antidepressant-like action of scopolamine in an animal model based on behavioral despair, namely, the tail suspension test (TST). It was found that AMPT induced a partial reduction in the antidepressant-like effect of scopolamine (0.3mg/kg) in the TST in C57BL/6 mice and that the effect of scopolamine was comparable to the effect of reboxetine (10mg/kg), which was used in this study as a reference drug. The attenuated antidepressant-like effect of scopolamine in AMPT-treated mice was observed in both its immediate (30min after administration) and prolonged (24h after administration) action in the TST. On the other hand, serotonin depletion by PCPA-pretreatment had no effect on the antidepressant effect of scopolamine (0.3mg/kg) either 30min or 24h after administration. Furthermore, a dose-dependent decrease in the immobility time of mice treated with a non-active dose of reboxetine (2mg/kg) together with non-active doses of scopolamine (0.03 and 0.1mg/kg) was found, suggesting a synergistic interaction between reboxetine and scopolamine in the TST. In contrast, a subeffective dose of the SSRI citalopram co-administered with subeffective doses of scopolamine did not induce significant changes in the behavior of mice in this test. Altogether, these data suggest that activation of the noradrenergic system might be involved in the antidepressant-like effect of scopolamine in the TST.

Antidepressant-like effects of scopolamine in mice are enhanced by the group II mGlu receptor antagonist LY341495.

Clinical studies have shown that the muscarinic receptor antagonist scopolamine induces a potent and rapid antidepressant effect relative to conventional antidepressants. However, potential undesirable effects, including memory impairment, partially limit the use of scopolamine in psychiatry. In the present study, we propose to overcome these limitations and enhance the therapeutic effects of scopolamine via administration in combination with the group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. Joint administration of sub-effective doses of scopolamine (0.03 or 0.1 mg/kg, i.p.) with a sub-effective dose of LY341495 (0.1 mg/kg, i.p.) induced a profound antidepressant effect in the tail suspension test (TST) and in the forced swim test (FST) in mice. This drug combination did not impair memory, as measured using the Morris water maze (MWM), and did not influence the locomotor activity of mice. Furthermore, we found that an AMPA receptor antagonist, NBQX (10 mg/kg), completely reversed the antidepressant-like activity of a mixture of scopolamine and LY341495 in the TST. However, this effect was not influenced by para-chlorophenylalanine (PCPA) pre-treatment, indicating a lack of involvement of serotonergic system activation in the antidepressant-like effects of jointly given scopolamine and LY341495. Therefore, the combined administration of low doses of the antimuscarinic drug scopolamine and the group II mGlu receptor antagonist LY341495 might be a new, effective and safe strategy in the therapy of depression.

Glutamate-Based Drug Discovery for Novel Antidepressants.

INTRODUCTION: Classic antidepressants that modulate monoaminergic systems are not sufficiently effective and require long systematic application. Recent studies suggest that substances that modulate glutamatergic system may produce an antidepressant effect which is not only faster but also more sustained. AREAS COVERED: In this paper, the authors summarize the results of studies on antidepressant action of ketamine in patients with severe refractory depression, which have demonstrated high efficacy in a very short time after a single dose. Due to the adverse effects of ketamine that substantially exclude it from the daily use by patients, efforts have been made to find other NMDA receptor antagonists, which could mimic the therapeutic effect of ketamine but without the side effects. Intensive studies to elucidate ketamine's mechanism of antidepressant action have also been conducted. Herein, the results of research showing that metabotropic glutamate (mGlu) receptors could be the target of novel antidepressants are also presented. EXPERT OPINION: The intensive preclinical and clinical research on NMDA and mGlu receptor ligands, which is currently going on, could contribute to the awaited breakthrough in the field of novel antidepressant drug discovery. This line of research may also lead to a new understanding of the biological basis of depression.

Group II mGlu receptor antagonist LY341495 enhances the antidepressant-like effects of ketamine in the forced swim test in rats.

RATIONALE: Numerous preclinical and clinical studies have reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist ketamine. Because ketamine induces several undesirable and dangerous effects, a variety of strategies have been suggested to avoid such effects. OBJECTIVES: Here, we propose to enhance the sub-effective doses of ketamine by co-administration with the group II metabotropic glutamate (mGlu) receptor antagonist LY341495. This compound potentially acts as an antidepressant via a mechanism similar to that of ketamine. METHODS: To investigate the rapid and sustained antidepressant-like effects of these drugs, we administered ketamine and LY341495 individually or in combination, 40 min and 24 h before the forced swim test (FST). RESULTS: We found that sub-effective doses of ketamine and LY341495, given jointly, induce significant antidepressant-like effects, at both 40 min and 24 h after administration. The results obtained using Western blot technique indicate that mammalian target of rapamycin (mTOR) pathway activation may be involved in the mechanism of this action. The effects of drugs, used at identical ranges of times and doses, on spontaneous locomotor activity in rats were excluded. Furthermore, the results obtained from the rota-rod test and the ketamine-induced hyperlocomotion test suggest a lack of potentially adverse effects from the combined administration of ketamine and LY341495 at doses previously used in the FST. CONCLUSION: Altogether, these data suggest that the joint administration of ketamine and LY341495 might be a noteworthy alternative to the use of solely ketamine in the therapy of depression.

Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc.

The rapid antidepressant response to the N-methyl-D-aspartate (NMDA) receptor antagonists is mediated by activation of the mammalian target of the rapamycin (mTOR) signaling pathway, an increase in the synthesis of synaptic proteins and formation of new synapses in the prefrontal cortex (PFC) of rats. Zinc (Zn), which is a potent NMDA receptor antagonist, exerts antidepressant-like effects in screening tests and models of depression. We focused these studies in investigating whether activation of the mTOR signaling pathway is also a necessary mechanism of the antidepressant-like activity of Zn. We observed that a single injection of Zn (5 mg/kg) induced an increase in the phosphorylation of mTOR and p70S6K 30 min and 3 h after Zn treatment at time points when Zn produced also an antidepressant-like effect in the forced swim test (FST). Furthermore, Zn administered 3 h before the decapitation increased the level of brain derived neurotrophic factor (BDNF), GluA1 and synapsin I. An elevated level of GluA1 and synapsin I was still observed 24 h after the Zn treatment, although Zn did not produce any effects in the FST at that time point. We also observed that pretreatment with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), H-89 (PKA inhibitor) and GF109203X (PKC inhibitor) blocked the antidepressant-like effect of Zn in FST in rats and blocks Zn-induced activation of mTOR signaling proteins (analyzed 30 min after Zn administration). These studies indicated that the antidepressant-like activity of Zn depends on the activation of mTOR signaling and other signaling pathways related to neuroplasticity, which can indirectly modulate mTOR function.

A novel mGlu4 selective agonist LSP4-2022 increases behavioral despair in mouse models of antidepressant action.

Numerous data have indicated that metabotropic glutamate (mGlu) receptor ligands may be potentially useful as novel antidepressant drugs (ADs). The Group III mGlu receptor has not been explored much because of the limited access to selective ligands, but some behavioral studies have indicated that modulating group III mGlu receptors may result in benefits for the therapy of depression. Here, we investigated the potential antidepressant-like effects of a new mGlu4 selective orthosteric agonist, LSP4-2022. We found that the drug induced pro-depressant effects in the tail suspension test (TST) and the forced swim test (FST) in mice at doses that did not change the locomotor activity of the animals. Additional experiments that used knock-out (KO) mice and aimed to verify the selectivity of LSP4-2022 revealed that the drug induced strong pro-depressant-like effects in mGlu7 KO mice but did not affect the behavior of mGlu4 KO mice in the TST, suggesting that the activation of the mGlu4 receptor plays a role in producing the pro-depressant activity of the tested drug. The results of our study indicate that the inhibition rather than activation of mGlu4 receptors might induce antidepressant effects, but this hypothesis should be verified using a selective mGlu4 receptor antagonist, which is currently not available.

NMDA antagonists under investigation for the treatment of major depressive disorder.

INTRODUCTION: Mood disorders, including depression, are becoming increasingly prevalent in the developed world. Furthermore, treatment of depression therapeutics, mainly influencing the serotonergic and adrenergic systems, is considered insufficient. The original NMDA-glutamate hypothesis mechanism of antidepressant action was first proposed ∼ 20 years ago. Since then, a number of preclinical and clinical studies have examined its rationale. AREAS COVERED: This review highlights the recent clinical evidence for the use of functional NMDA receptor antagonists as antidepressants. Furthermore, the authors present the mechanism(s) of antidepressant action derived mostly from preclinical paradigms. EXPERT OPINION: Currently, clinical studies mostly use ketamine (a noncompetitive high-potency NMDA antagonist) as an agent for rapid relief of depressive symptoms. However, due to the ketamine-induced psychotomimetic effects, new NMDA receptor antagonists (modulators) are continuously being introduced for rapid antidepressant action, especially for use in treatment-resistant patients. Recent clinical reports for the use of CP-101,606, MK-0657 (selective GluN2B subunit NMDA receptor antagonists), GLYX-13 and d-cycloserine (glycine site partial agonists) are optimistic but await further support.

Prolonged administration of antidepressant drugs leads to increased binding of [(3)H]MPEP to mGlu5 receptors.

Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs.

Activation of the mTOR signaling pathway in the antidepressant-like activity of the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082 in the FST in rats.

Clinical studies have demonstrated rapid and long-lasting antidepressant effects of ketamine in depressive patients. It has been proposed that these effects are related to changes in synaptogenesis in the mechanism involving mammalian target of rapamycin (mTOR) activation. Similar mechanisms have been proposed for a group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. We aimed to investigate whether other mGlu receptor ligands that produce antidepressant-like effects, namely, the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082, induce the activation of mTOR signaling in the prefrontal cortex (PFC) in rats. AMN082 administered 60 min before the test increased the levels of pmTOR and pp70S6K, and the mTORC1 antagonist rapamycin reversed AMN082-induced changes in the forced swim test (FST) in rats. Furthermore, AMN082 administered 23 h before the decapitation of the rats increased the levels of synapsin I and GluR1, although it did not produce any effect in the FST at the same time point. However, MTEP induced a rapid but unsustained antidepressant-like effect, which was not related to the activation of the mTOR cascade. Finally, the antidepressant-like effects of MTEP or AMN082 were not antagonized by NBQX. In summary, the antidepressant-like activity of MTEP did not depend on the activation of mTOR signaling. However, we observed a unique feature of the mechanism of AMN082. The drug stimulated the mTOR signaling pathway and synaptic protein levels (like ketamine), while it did not induce a sustained antidepressant effect and its action was not directly dependent on AMPA receptor activation (as in classic antidepressants (ADs)).