Antidepressant-like actions of the mGlu2/3 receptor antagonist TP0178894 in the chronic social defeat stress model: Comparison with escitalopram.

The metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists are reported to produce ketamine-like rapid-acting and sustained antidepressant-like effects in rodents. In this study, we compared the effects of single administration of the new mGlu2/3 receptor antagonist TP0178894 and the selective serotonin reuptake inhibitor (SSRI) escitalopram in the chronic social defeat stress (CSDS) model of depression, a model which has been shown to be resistant to treatment with a single dose of SSRI. In the tail suspension test and forced swimming test, high dose (3.0 mg/kg) of TP0178894 significantly attenuated the increased immobility time of these tests in CSDS susceptible mice, compared with vehicle-treated mice. In contrast, low doses (0.3 and 1.0 mg/kg) of TP0178894 and escitalopram (10 mg/kg) did not alter the increased immobility time of these two tests. In the sucrose preference test, TP0178894 (3.0 mg/kg) significantly improved the reduced sucrose preference of CSDS susceptible mice, three and seven days after a single dose. In addition, Western blot analyses showed that TP0178894 (3.0 mg/kg), but not low doses of TP0178894 and escitalopram, significantly attenuated the reduced expression of synaptic proteins [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA1) and postsynaptic density protein 95 (PSD-95)] in the prefrontal cortex from CSDS susceptible mice. This study suggests that TP0178894 shows rapid-acting and sustained antidepressant-like effects in CSDS model, as ketamine does.

Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents.

BACKGROUND: TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects. METHODS: This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15-400 mg TS-161) and 10-day multiple-ascending dose (50-150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161. RESULTS: Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness. CONCLUSIONS: The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.

Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study.

Vasopressin 1B (V1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.

Depression-resistant Phenotype in Mice Overexpressing Regulator of G Protein Signaling 8 (RGS8).

Regulator of G protein signaling (RGS) proteins are negative regulators of heterotrimeric G proteins that act by accelerating Gα-mediated GTPase activity to terminate G protein-coupled receptor-associated signaling. RGS8 is expressed in several brain regions involved with movement and mood. To investigate the role of RGS8 in vivo, we generated transgenic mice overexpressing brain RGS8 (RGS8tg). RGS8 gene and protein expressions were examined by real-time PCR and immunohistochemistry, respectively, and a significant increase in RGS8 protein was detected in the hippocampal CA1 region compared with wild-type mice (WT). We characterized the phenotypic traits, and found that RGS8tg showed decreased depressive-like behavior in the forced swimming test (FST). Previously, RGS8 was identified as a potent negative regulator of melanin-concentrating hormone receptor 1 (MCHR1), whose activation is mainly involved in energy homeostasis and emotional processing. Interestingly, acute oral administration of MCHR1 antagonist SNAP94847 did not have antidepressant-like effects on RGS8tg in the FST, but did show antidepressant effects on WT. In contrast, selective noradrenaline reuptake inhibitor desipramine had a significant effect on RGS8tg in the FST. MCHR1 is enriched in a subset of primary cilia, as sensory organelles that mediate extracellular signaling. Immunohistochemical analyses revealed significant elongation of MCHR1-positive cilia in the CA1 region of RGS8tg compared with WT. Taken together, these findings suggest that RGS8 participates in modulation of depression-like behavior through ciliary MCHR1 expressed in the CA1 region. The present study may support the possible modulation of RGS8 function in mood disorders.

5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2/3 receptor antagonist in mice.

We previously reported that serotonergic transmission is involved in the antidepressant effects of metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists. However, the detailed underlying mechanisms had not yet been explored. In the present study, we investigated the role of the 5-HT1A receptor and its signaling cascade in the medial prefrontal cortex (mPFC) in the antidepressant effects of LY341495, an mGlu2/3 receptor antagonist. LY341495 significantly reduced the immobility time in the forced swimming test which sustained for 24 h after administration. The antidepressant effect of LY341495 was attenuated by either intraperitoneal or intra-mPFC injection of WAY100635, a 5-HT1A receptor antagonist. Among the signaling cascades mediated by the 5-HT1A receptor, the role of phosphoinositide-3 kinase (PI3K)/Akt signaling, which has a critical role in neuroplasticity, was investigated. The sustained antidepressant effect of LY341495 was blocked by intra-mPFC injection of LY294002, a PI3K inhibitor. LY341495 increased the phosphorylation of Akt in the mPFC, which was blocked by both intra-mPFC injection of WAY100635 and LY294002. Thus, LY341495 activates PI3K/Akt signaling, presumably via stimulation of the 5-HT1A receptor in the mPFC, to exert its sustained antidepressant effect. Involvement of mechanistic target of rapamycin complex-1 (mTORC1) signaling was also demonstrated, as the sustained antidepressant effects of LY341495 was attenuated by intra-mPFC injection of rapamycin, an mTORC1 inhibitor. Finally, the sustained antidepressant effect of LY341495 was also attenuated by silencing of the dorsal raphe nucleus (DRN) neurons. These results suggest that stimulation of the 5-HT1A receptor in the mPFC and its signaling cascade, PI3K/Akt/mTORC1 signaling mediate the sustained antidepressant effect of LY341495, and that activation of the DRN neurons is also involved in these processes.

Role of 5-HT1A Receptor Stimulation in the Medial Prefrontal Cortex in the Sustained Antidepressant Effects of Ketamine.

Background: We previously reported that serotonergic transmission plays an important role in antidepressant effects of ketamine. However, detailed mechanisms have not been elucidated. Among the serotonin receptor subtypes, the serotonin1A receptor in the medial prefrontal cortex has an important role in depression. Here, we investigated the role of the medial prefrontal cortex serotonin1A receptor and its signaling mechanism in the antidepressant effects of ketamine. Methods: The role of serotonin1A receptor-mediated signaling mechanism (phosphoinositide-3 kinase/Akt) in the medial prefrontal cortex was examined in the mouse forced swimming test and western blotting. Results: Ketamine exerted antidepressant effects that lasted for 24 hours, and the sustained antidepressant effects were attenuated by intra-medial prefrontal cortex injection of a serotonin1A receptor antagonist, WAY100635. The sustained antidepressant effects were mimicked by intra- medial prefrontal cortex, but not systemic, administration of a serotonin1A receptor agonist, (±)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT). The sustained antidepressant effects of ketamine and 8-OH-DPAT were abrogated by intra- medial prefrontal cortex injection of a phosphoinositide-3 kinase inhibitor. Ketamine increased the phosphorylation of Akt in the medial prefrontal cortex at 60 minutes after administration, which was blocked by a serotonin1A receptor antagonist and a phosphoinositide-3 kinase inhibitor. Furthermore, the sustained antidepressant effects of ketamine and 8-OH-DPAT were attenuated by pretreatment of intra-medial prefrontal cortex injection of a mechanistic target of rapamycin complex-1 inhibitor. Conclusions: These results indicate that selective stimulation of the medial prefrontal cortex serotonin1A receptor and subsequent activation of the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin complex-1 pathway may be necessary for ketamine to exert the sustained antidepressant effects, and that this mechanism could be targeted to develop a novel and effective approach for treating depression.

Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine.

The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence suggests that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that (R)-ketamine exerted longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.

The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN.

We have reported the antidepressant effects of both metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and ketamine in several animal models, and proposed that serotonergic (5-HTergic) transmission is involved in these actions. Given that the projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN), where the majority of serotonin (5-HT) neurons exist, are reportedly involved in the antidepressant effects, in this study, we investigated using the forced swimming test (FST) of C57BL/6J male mice, the role of 5-HT neurons in the DRN regulated by the mPFC-DRN projections in the antidepressant effects of an mGlu2/3 receptor antagonist, LY341495, and ketamine. Following systemic administration/microinjection into the mPFC, both LY341495 and ketamine were found to exert antidepressant effects in the FST, and the effects were attenuated by depletion of 5-HT by treatment with an inhibitor of 5-HT synthesis, PCPA. The antidepressant effects of LY341495 and ketamine were also blocked by systemic administration/microinjection into the mPFC of an AMPA receptor antagonist, NBQX. Moreover, systemic administration/microinjection into the mPFC of LY341495 and ketamine significantly increased the c-Fos expression in the 5-HT neurons in the DRN, and the effect of systemic administration of these drugs on the neuronal c-Fos expression was attenuated by microinjection of NBQX into the mPFC. Our findings suggest that activation of 5-HT neurons in the DRN regulated by stimulation of the AMPA receptor in the mPFC may be involved in the antidepressant effects of an mGlu2/3 receptor antagonist and ketamine.

Antidepressant/anxiolytic potential and adverse effect liabilities of melanin-concentrating hormone receptor 1 antagonists in animal models.

Melanin-concentrating hormone receptor 1 (MCH1 receptor) is known to be involved in the control of mood and stress, in addition to the regulation of feeding. Here, we report further evidence that the blockade of the MCH1 receptor exhibits antidepressant and anxiolytic-like effects in a variety of animal models using TASP0382650 and TASP0489838, newly synthesized MCH1 receptor antagonists, with different scaffolds. Both TASP0382650 and TASP0489838 exhibited high affinities for human MCH1 receptor with IC50 values of 7.13 and 3.80nM, respectively. Both compounds showed potent antagonist activities at the MCH1 receptor, as assessed using MCH-increased [(35)S]GTPγS binding to human MCH1 receptor and an MCH-induced [Ca(2+)]i assay in rat MCH1 receptor expressing cells. In contrast, neither TASP0382650 nor TASP0489838 showed an affinity for the MCH2 receptor, another MCH receptor subtype. The oral administration of TASP0382650 or TASP0489838 significantly reduced the immobility time during the forced swimming test in rats, and reduced hyperemotionality induced by an olfactory bulbectomy, both of which are indicative of an antidepressant-like potential. In the olfactory bulbectomy model, the antidepressant effect of TASP0382650 appeared following a single administration, suggesting a faster onset of action, compared with current medications. Moreover, both TASP0382650 and TASP0489838 exhibited anxiolytic effects in several animal models of anxiety. In contrast, both TASP0382650 and TASP0489838 did not affect spontaneous locomotor activity, motor function, spatial memory during the Morris water maze task, or the convulsion threshold to pentylenetetrazole. These findings provide additional evidence that the blockade of the MCH1 receptor exhibits antidepressant- and anxiolytic activities with no adverse effects in experimental animal models.

Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia.

RATIONALE: Since the hypofunction of the N-methyl-D-aspartate (NMDA) receptor is known to be involved in the pathophysiology of schizophrenia, the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophrenia. OBJECTIVES: We investigated the efficacy of a glycine transporter 1 (GlyT1) inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms, both of which are poorly managed by current antipsychotics. RESULTS: A newly synthesized GlyT1 inhibitor, 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (TASP0315003) significantly improved cognitive deficit induced by MK-801 in the object recognition test in rats. Likewise, TASP0315003 significantly improved MK-801 impaired cognition in the social recognition test in rats and also enhanced social memory in treatment-naïve rats. In addition, repeated phencyclidine (PCP) treatment reduced the social interaction of paired mice, which may reflect negative symptoms such as social withdrawal, and both acute and sub-chronic treatment with TASP0315003 reversed the reduction in social interaction induced by PCP. Moreover, TASP0315003 additionally exhibited an antidepressant effect in the forced swimming test in rats. In contrast, TASP0315003 did not affect spontaneous locomotor activity or rotarod performance and did not induce catalepsy, indicating that TASP0315003 does not cause sedation or motor dysfunction, which is sometimes observed with the use of current antipsychotics. CONCLUSIONS: These results suggest that GlyT1 inhibitors including TASP0315003 may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects.

Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test.

RATIONALE: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor stimulation has been proposed to be a common neural mechanism of metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and an N-methyl-D-aspartate receptor antagonist, ketamine, exerting antidepressant effects in animal models. AMPA receptor stimulation has also been shown to mediate an increase in the extracellular level of serotonin (5-HT) in the medial prefrontal cortex by an mGlu2/3 receptor antagonist in rats. However, involvement of the serotonergic system in the actions of mGlu2/3 receptor antagonists and ketamine is not well understood. OBJECTIVES: We investigated involvement of the serotonergic system in the effects of an mGlu2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and ketamine in a novelty-suppressed feeding (NSF) test in mice. RESULTS: The intraperitoneal administration of LY341495 or ketamine at 30 min prior to the test significantly shortened latency to feed, which was attenuated by an AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydr-obenzo[f]quinoxaline-7-sulfonamide (NBQX). The effects of LY341495 and ketamine were no longer observed in mice pretreated with a tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effects of LY341495 and ketamine were blocked by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635), but not by a 5-HT2A/2C receptor antagonist, ritanserin. Likewise, an AMPA receptor potentiator, 2,3-dihydro-1,4-benzodioxin-7-yl-(1-piperidyl)methanone (CX546), shortened latency to feed in the NSF test, which was prevented by depletion of 5-HT and blockade of 5-HT1A receptor. CONCLUSIONS: These results suggest that AMPA receptor-dependent 5-HT release and subsequent 5-HT1A receptor stimulation may be involved in the actions of an mGlu2/3 receptor antagonist and ketamine in the NSF test.

Effects of ketamine and LY341495 on the depressive-like behavior of repeated corticosterone-injected rats.

In the present study, to further validate repeated corticosterone (CORT)-treated rats as a treatment-resistant depression (TRD) model, we first examined the effect of ketamine, which is known to be effective for the treatment of TRD, on the depressive-like behavior of CORT-treated rats. In this model, ketamine significantly reduced the increased immobility time of CORT-treated rats during the forced swim test (FST), indicating that its efficacy against TRD could be detected using this model. We next examined the effect of LY341495, a group ΙΙ metabotropic glutamate (mGlu2/3) receptor antagonist, in this model to evaluate its potential for the alleviation of TRD. LY341495, similar to ketamine, attenuated the increased immobility time of CORT-treated rats during the FST. Therefore, these results suggest that mGlu2/3 receptor antagonists might be effective for patients with depression, including TRD.

Effect of an mGlu2/3 receptor antagonist on depressive behavior induced by withdrawal from chronic treatment with methamphetamine.

Withdrawal from chronic treatment with a psychostimulant precipitates behavioral and physiological conditions similar to the symptoms of major depressive disorder (MDD). Accumulated studies have indicated that withdrawal from a psychostimulant in rodents elicits depressive phenotypes including despair and anhedonia. Recently, the modulation of the group II metabotropic glutamate (mGlu2/3) receptor has been proposed as a novel therapeutic approach to MDD. In the present study, we investigated the effect of an mGlu2/3 receptor antagonist, LY341495, on the depressive behavior induced by withdrawal from chronic treatment with a psychostimulant, methamphetamine (MAP) (5.0mg/kg/day×5 days). The rats were then tested for depressive behavior using the forced swimming test. Withdrawal from chronic treatment with MAP increased the immobility time during the forced swimming test, indicating increased depressive behavior. Systemically administered LY341495 counteracted the depressive behavior induced by withdrawal from chronic treatment with MAP. Moreover, we found that the microinjection of LY341495 into the nucleus accumbens (NAc) also counteracted the increase in the immobility time caused by withdrawal from chronic treatment with MAP. Taken together, the present results suggested that the blockade of the mGlu2/3 receptor may prevent the depressive symptoms induced by withdrawal from a psychostimulant and that the blockade of the mGlu2/3 receptor in the NAc may contribute to the antidepressant-like effects of the mGlu2/3 receptor antagonist in this test.

Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression.

We previously revealed that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor and mammalian target of rapamycin signaling contributed to the antidepressant-like effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists, suggesting that the signaling pathway may be similar to the molecular mechanisms underlying the antidepressant-like action of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that exertes rapid and sustained antidepressant effects in patients with depressive disorder. Although brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling reportedly participates in the antidepressant-like effects of ketamine, the involvement of BDNF/TrkB signaling in the action of mGlu2/3 receptor antagonists has not been investigated. We therefore examined whether the activation of BDNF/TrkB signaling is required for the antidepressant-like effects of LY341495, an mGlu2/3 receptor antagonist, in animal models of depression such as the tail suspension test (TST) and the novelty-suppressed feeding test (NSFT). The administration of LY341495 at 30 min prior to the test exerted antidepressant-like effects (acute effects) lasting for at least 24 h (sustained effects) when evaluated using the TST and NSFT. Pretreatment with K252a, a TrkB tyrosine kinase inhibitor, blocked the sustained, but not the acute, effects of LY341495. These results suggest that BDNF/TrkB signaling may be involved in the sustained antidepressant-like effects of LY341495, as observed for ketamine treatment.

Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test.

Accumulated evidence indicates that metabotropic glutamate 5 (mGlu5) receptor blockade exerts antidepressant-like and anxiolytic-like effects in several animal models. The novelty-suppressed feeding (NSF) test is used to measure anxiety-induced hypophagia in rodents. Anxiogenic-like behavior can be counteracted by acute treatment with anxiolytics or chronic treatment with antidepressants. The objective of the present study was to investigate the effect of an mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), using the NSF test and to investigate the mechanisms underlying the effects of MPEP. The administration of MPEP at 1 h prior to testing significantly shortened the latency period until feed (an acute effect), and this effect lasted for 24 h (a sustained effect), similar to the results observed using the N-methyl-D-aspartate receptor antagonist ketamine. Pretreatment with a protein synthesis inhibitor, anisomycin, blocked the sustained, but not the acute, effects of MPEP, suggesting the involvement of new protein synthesis in the sustained effect of MPEP. In addition, the sustained effect of MPEP in the NSF test was partially abolished by pretreatment with a mammalian target of rapamycin (mTOR) antagonist, rapamycin. In contrast, a tropomyosin-related kinase, the tyrosine kinase inhibitor K252a, did not counteract the sustained effects of MPEP in this test. Taken together, these results are the first report to demonstrate that the blockade of the mGlu5 receptor exerted acute and sustained effects in the NSF test and that new protein synthesis may contribute to the sustained effects of MPEP, which may not mediate brain-derived neurotrophic factor-mTOR signaling.

Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists.

Growing evidence has indicated that the blockade of group II metabotropic glutamate (mGlu2/3) receptor exerts antidepressant-like effects in several animal models of depression. However, the molecular mechanisms underlying the action of mGlu2/3 receptor antagonists are not well understood. Here, we investigated the involvement of mammalian target of rapamycin (mTOR) signaling in the acute and sustained antidepressant-like effects of mGlu2/3 receptor antagonists such as (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). Mice were subjected to a tail suspension test (TST) to assess the acute and sustained antidepressant-like effects. We evaluated the effect of rapamycin, an mTOR antagonist, on the acute and sustained antidepressant-like effects of mGlu2/3 receptor antagonists. Both MGS0039 and LY341495 exerted antidepressant-like effects, as evaluated using the TST; these effects were sustained for 24 h. Pretreatment with rapamycin blocked the sustained, but not the acute, antidepressant-like effects of mGlu2/3 receptor antagonists, as observed in ketamine. The present result suggests that the blockade of the mGlu2/3 receptor may activate mTOR signaling, and that the activation of mTOR signaling may contribute to the sustained antidepressant-like effects of mGlu2/3 receptor antagonists.

Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression.

A growing body of evidence has suggested that the dysfunction of glutamatergic systems plays a pivotal role in major depressive disorder (MDD). In clinical studies, an N-methyl-d-aspartate receptor antagonist, ketamine, was shown to exert both rapid and sustained antidepressant effects in patients with treatment-resistant MDD. The objective of the present study was to confirm the rapid onset of action of ketamine and to investigate the mechanisms underlying both the rapid and sustained antidepressant-like effects of ketamine in rodent models of depression. The intraperitoneal administration of ketamine (10mg/kg) 30min prior to testing significantly reduced the number of escape failures in the learned helplessness (LH) paradigm in rats in which currently prescribed antidepressants exerted an effect only after repeated administrations. Ketamine also significantly reduced the immobility time in the tail suspension test (TST), and this effect lasted for 72h, indicating that ketamine may possess a sustained antidepressant-like effect. The rapid antidepressant-like effects of ketamine in both the LH paradigm and the TST were significantly blocked by subcutaneous treatment with 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX), an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. In addition, the sustained antidepressant-like effect of ketamine in the TST was partially abolished by treatment with NBQX. In conclusion, we confirmed the faster onset of the action of ketamine, compared with clinically prescribed antidepressants. Moreover, the present results suggested that direct AMPA receptor activation may play an important role in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression, although other mechanisms might be involved in the sustained action.

Pharmacological characterization of repeated corticosterone injection-induced depression model in rats.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in patients with psychotic major depression (PMD), and a higher rate of cortisol hypersecretion is observed in PMD than in nonpsychotic patients. Approximately 19% of patients who meet the criteria for major depressive disorder (MDD) have psychotic features. Accumulated studies have indicated that repeated corticosterone (CORT) injections induce depressive behavioral and neurochemical manifestations in rodents. However, the pharmacological characterization of this model has not been fully established. In the present study, we investigated the pharmacological characteristics of this model. Rats received CORT injections (20 mg/kg, subcutaneously), once per day for 21 consecutive days prior to a behavioral test. The rats were then tested for depressive behavior using a forced swimming test. The repeated CORT injections increased the immobility time in the forced swimming test, indicating an increase in depressive-like behavior. An acute treatment with a glucocorticoid receptor antagonist, mifepristone, counteracted the depressive-like behavior. In contrast, an acute treatment with a selective serotonin reuptake inhibitor (SSRI), fluvoxamine, and a tricyclic antidepressant (TCA), imipramine, did not have any effect on this condition, while a combination of fluvoxamine and risperidone exerted an antidepressant-like effect. This observation is of interest in the light of the clinical findings that a combination of antidepressants and antipsychotics, but not SSRIs and TCAs, is effective for the treatment of patients with PMD. Based on previous findings and the present results, this model could be used as an animal model of PMD and may be useful for evaluating the antidepressant-like potential of compounds targeting the HPA axis.

Effects of agents targeting glutamatergic systems on marble-burying behavior.

Accumulating evidence has implicated glutamatergic systems in psychiatric disorders. Abnormalities in glutamatergic systems have consistently been identified in obsessive-compulsive disorder (OCD). Marble-burying behavior has been described in literature as a potentially useful measure for modeling OCD in mice. However, involvement of glutamatergic systems in marble-burying behavior has largely remained unexplored. Here, the effects of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator, CX546, and an NR2B subunit-containing N-methyl-D-aspartate (NMDA) receptor antagonist, Ro25-6981, were examined using a marble-burying test. Treatment with highest dose (30.0mg/kg) of CX546 significantly inhibited the marble-burying behavior. Moreover, treatment with Ro25-6981 also significantly reduced the marble-burying behavior. In contrast, both drugs did not affect locomotor activity in mice. The present results suggest that glutamatergic systems might be related to marble-burying behavior. Furthermore, agents targeting glutamateric systems such as an AMPA receptor potentiator and an NR2B receptor antagonist, may be useful in treating OCD.