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.

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.

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

Vasopressin 1B (V) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V 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 V 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.

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).

5-HT 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-HT receptor and its signaling cascade in the medial prefrontal cortex (mPFC) in the antidepressant effects of LY341495, an mGlu2/3 receptor antagonist.

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.

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

The rapid-acting and long-lasting antidepressant effects of ()-ketamine have recently gained much attention. Although ()-ketamine has been studied as an active isomer, recent evidence suggests that ()-ketamine exhibits longer-lasting antidepressant effects than ()-ketamine in rodents. However, the antidepressant potential of ()-ketamine has not been fully addressed.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

An arginine vasopressin V1b antagonist, SSR149415 elicits antidepressant-like effects in an olfactory bulbectomy model.

Olfactory bulbectomized (OB) rats have been considered to serve as a useful animal model of depression in terms of behavioral, neurochemical, and neuroendocrine alterations, which reflect symptoms of patients with major depression. These behavioral and neurochemical changes in OB rats are normalized by the chronic administration of antidepressants. Recently, it has been reported that the compounds acting on stress-related peptide receptors such as an arginine vasopressin 1b (V(1b)) receptor antagonist and corticotropin-releasing factor (CRF) 1 receptor antagonists have antidepressant-like effects in several animal models.

Effects of metabotropic glutamate 2/3 receptor antagonists in the stress-induced hyperthermia test in singly housed mice.

Rationale: The stress-induced hyperthermia (SIH) test in mice has been widely used as models including some physiological aspects of psychiatric disorders. Mediated by the autonomic nervous system, SIH is commonly known to occur both before and during exposure to stress-inducing or anxiogenic situations. Recently, modulation of the group II metabotropic glutamate (mGlu) 2/3 receptor has been proposed as a novel therapeutic approach for psychiatric disorders.

The pituitary mediates the anxiolytic-like effects of the vasopressin V1B receptor antagonist, SSR149415, in a social interaction test in rats.

A vasopressin V(1B) receptor antagonist has been shown to exhibit anxiolytic effects in a variety of animal models of anxiety. In the present study, we examined the involvement of the pituitary in the anxiolytic effects of a vasopressin V(1B) receptor antagonist by conducting a social interaction test in rats. In the sham-operated rats, both the vasopressin V(1B) receptor antagonist SSR149415 and the benzodiazepine chlordiazepoxide significantly increased the social behavior of a pair of unfamiliar rats, and the blood adrenocorticotropic hormone levels were markedly increased during the social interaction test.

Separation-induced ultrasonic vocalization in rat pups: further pharmacological characterization.

In rat pups, ultrasonic vocalizations were emitted in response to separation from the mothers, littermates, and nest. It has been suggested that these separation-induced ultrasonic vocalizations (SIV) in rat pups form one of the animal models of anxiety. The primary aim of the present study is to investigate the effect of the compounds acting on stress-related peptide receptors such as a vasopressin V1b receptor antagonist and a corticotropin-releasing factor CRF1 receptor antagonist in rat pup SIV.

Altered food-anticipatory activity rhythm in Cryptochrome-deficient mice.

In nocturnal rodents, restricted feeding to daytime (RF) causes feeding-associated diurnal locomotor activity that persists for the next 1-2 days when food is withheld. Along with this anticipatory behavior, the expression pattern of clock genes such as mPer1 and mPer2 changes from a nocturnal to diurnal pattern in the liver and cerebral cortex but not in the suprachiasmatic nucleus (SCN). Whether the molecular clockwork, in which mCry1 and mCry2 genes are essential components, is involved in food-anticipatory circadian rhythms is unknown.