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.

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 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. OBJECTIVES: In the present study, we evaluated the efficacy of selective mGlu2/3 receptor antagonists and an mGlu2/3 receptor agonist in the SIH test. RESULTS: mGlu2/3 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. CONCLUSIONS: Taken 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.

Effects of early weaning on anxiety and autonomic responses to stress in rats.

Environmental stimuli affect various aspects of the early physical and behavioral development in rats. One of the most important events in the early stage of life is weaning, and we recently reported that precocious weaning augments anxiety and aggressiveness in rats and mice. In the present study, we investigated the autonomic responses to stress in two groups of rats: the early-weaned group (weaned at 16 days of age), and the normally weaned group (weaned at 30 days) as a control. First, the early and normally weaned rats were subjected to an elevated plus-maze test to assess their anxiety levels. It was confirmed that early-weaned male rats, but not the females, showed a lower frequency of entry into and shorter duration of stay in the open arms of the maze compared to the normally weaned rats. Subsequently, the two groups were either placed in a novel clean cage or exposed to an unfamiliar conspecific, and their heart rates and core body temperatures were monitored to evaluate their autonomic stress responses. There was an exacerbation of autonomic responses, such as stress-induced hyperthermia and tachycardia, and an alternation of behavioral responses, including increased sniffing, and decreased grooming and resting. These effects of early weaning were significant only in males. In contrast, when rats encountered an unfamiliar individual, no significant differences were observed between the two groups in either sex. This suggests that stimuli emanating from an unfamiliar intruder were too intense to detect the augmentation of stress responses in the early-weaned rat. The results of the present study demonstrate that precocious weaning augments, not only behavioral but also autonomic responses, to stressful conditions with sexually dimorphic patterns, i.e. more profoundly in males than in females.

An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats.

RATIONALE: Abnormalities of glutamatergic neurotransmission have been reportedly observed in psychiatric disorders. Previously, we demonstrated that (1R, 2R, 3R, 5R, 6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) is a selective antagonist for group II metabotropic glutamate receptors (mGluR2/3), and that it exerted antidepressant effects in some animal behavioral tests. OBJECTIVES: In the present study, we provide additional evidence that MGS0039 exhibits antidepressant and anxiolytic effects in experimental rodent models, which are predictive of clinical efficacy. METHODS: The learned helplessness (LH) paradigm, which is a common model used to examine the depressive state, was used to assess antidepressant effects of MGS0039. Moreover, anxiolytic effects of MGS0039 were investigated in the conditioned fear stress (CFS) model, which represents emotional abnormality, including anxiety. RESULTS: Intraperitoneal administration of MGS0039 (10 mg/kg) to rats for 7 days elicited a significant reduction in escape failures in the LH paradigm. In addition, rats treated with MGS0039 (2 mg/kg) showed significantly attenuated freezing behavior in a CFS model, indicating the anxiolytic-like potential of MGS0039. CONCLUSIONS: These results suggest that the blockade of mGluR2/3 with MGS0039 may be effective in the treatment of depressive and anxiety disorders.