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Melanin-concentrating hormone (MCH) is a cyclic peptide produced in the lateral hypothalamus. It has been implicated in a number of physiological processes including feeding behavior, energy balance, and the regulation of emotional states. (1-10 mg/kg) significantly reduced immobility time in the forced swimming test in rats, indicating antidepressantlike effects. Both ATC0065 and ATC0175 significantly reversed swim stress-induced anxiety in the elevated plus-maze test in rats and stress-induced hyperthermia in mice. ATC0175 significantly increased social interaction between unfamiliar rats and reduced separation-induced vocalizations in guinea pig pups, indicating anxiolytic potential. In contrast, ATC0065 and ATC0175 did not affect spontaneous locomotor activity or rotarod performance in rats. These findings indicate that ATC0065 and ATC0175 are potent and orally active MCHR1 antagonists with anxiolytic and antidepressant activity in rodents.Melanin-concentrating hormone (MCH) is a cyclic neuropeptide originally isolated from salmon pituitary (Kawaguchi et al., 1983). In mammals, MCH is produced predominantly by neurons in the lateral hypothalamus and zona incerta with extensive projections throughout the brain (Bittencourt et al., 1992). This expression pattern supports a role for MCH in numerous physiological processes including motivated behavior, stress responses, regulation of neuroendocrine function, and feeding.Several groups independently identified a G protein-coupled receptor, SLC-1/GPR24, as an MCH receptor (MCHR1) (Bachner et al., 1999;Chambers et al., 1999;Lembo et al., 1999;Saito et al., 1999;Shimomura et al., 1999), and MCHR2 was identified subsequently on the basis of the sequence homology to MCHR1 Hill et al., 2001;Mori et al., 2001;Sailer et al., 2001). Potential physiological functions of MCHR2 have not been elucidated due to the species-specific expression of the receptor (Tan et al., 2002); therefore, current research has focused on MCHR1.There are several lines of evidence implicating MCHR1 in feeding and energy homeostasis. MCHR1 mRNA is increased Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

These results suggest that the blockade of mGluR2/3 with MGS0039 may be effective in the treatment of depressive and anxiety disorders.

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The present results show that stimulation of the glycine modulatory sites on the NMDA receptor either directly with D: -serine or by blocking glycine transporter-1 enhances social memory and may be an effective approach for the treatment of the cognitive dysfunction observed in schizophrenic patients.

BACKGROUND AND PURPOSEVasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325. EXPERIMENTAL APPROACHWe investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models. KEY RESULTSBoth TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats). CONCLUSIONTASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.

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