Michihiko Iijima

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.

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.

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.

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.

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. The secondary objective is to establish further confirmation of the predictive validity of SIV testing. Both the V1b receptor antagonist SSR149415 and the CRF1 receptor antagonist CP154,526 reduced SIV, suggesting antagonists for stress-related peptide receptors are effective in this model. Furthermore, as with selective serotonin reuptake inhibitors such as fluvoxamine and paroxetine, SIV was also reduced by the serotonin and noradrenaline reuptake inhibitor milnacipran and the metabotropic glutamate receptor 5 antagonist MPEP, while desipramine was without effect. Thus, the present experiment highlights the important role of the stress-related peptide systems as well as of the serotonergic systems in SIV. Moreover, the present data support the usefulness of SIV for evaluating the anxiolytic-like activity of mechanically diverse compounds.

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.

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

RationaleThe 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.ObjectivesIn the present study, we evaluated the efficacy of selective mGlu2/3 receptor antagonists and an mGlu2/3 receptor agonist in the SIH test.ResultsmGlu2/3 receptor antagonists such as MGS0039 and LY341495 significantly and dose-dependently reduced SIH without affecting basal rectal temperatures. In contrast, mGlu2/3 receptor agonists such as MGS0008 were ineffective in the SIH test. The attenuation of SIH by MGS0039 was significantly blocked by pretreatment with WAY100635, a serotonin 1A receptor antagonist. In contrast, an AMPA receptor potentiator, CX546 failed to reduce the SIH.ConclusionsTaken together, these results suggest that the blockade of mGlu2/3 receptor may prevent stress-induced autonomic hyperactivity, and that stimulation of the postsynaptic serotonin 1A receptor, but not AMPA receptor, may be involved in this action.

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.

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. Here, the effects of acute and chronic (14 days) treatment with a V(1b) receptor antagonist (SSR149415) and a CRF1 receptor antagonist (CP-154,526) were examined in olfactory bulbectomy-induced hyperemotionality. Oral acute treatment with SSR149415 or CP-154,526 did not affect olfactory bulbectomy-induced hyperemotionality. In contrast, oral chronic treatment with SSR149415 (10 and 30 mg/kg) or CP-154,526 (10 mg/kg) significantly reduced hyperemotionality. The present results suggest that stress-related peptides such as arginine vasopressin and CRF might be implicated in olfactory bulbectomy-induced hyperemotionality. Furthermore, blockade of the V(1b) receptor or the CRF1 receptor may be useful in treating subjects suffering from chronic stressful conditions.

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.