Anxiolytic- and Antidepressant-Like Profile of ATC0065 and ATC0175: Nonpeptidic and Orally Active Melanin-Concentrating Hormone Receptor 1 Antagonists

Abstract

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.

Melanin-Concentrating Hormone-1 Receptor Modulates Neuroendocrine, Behavioral, and Corticolimbic Neurochemical Stress Responses in Mice

“…MCH injected directly into the lateral ventricle or the PVN stimulated the HPA axis (Jezova et al, 1992;Kennedy et al, 2003), and MCHR1 antagonists resembled known antidepressant and anxiolytic drugs (Borowsky et al, 2002;Chaki et al, 2005). Our data support these findings and expand on them by demonstrating a direct relationship between the anxiogenic effects of MCH and the reversal of these effects by selective MCHR1 blockade.…”

“…infusion of MCH was reported to have either anxiogenic- (Gonzalez et al, 1996) or anxiolytic-like (Kela et al, 2003;Monzon and De Barioglio, 1999;Monzon et al, 2001) effects. Finally, novel MCHR1 antagonists blocked MCH-induced release of corticotrophin-releasing factor (Kennedy et al, 2003), and resembled known anxiolytics and antidepressants in animal models (Borowsky et al, 2002;Chaki et al, 2005).…”

Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

“…Reduced anxiety-like behavior following acute treatment with SNAP-7941 (Borowsky et al, 2002) and ATC0065/0175 (Chaki et al, 2005) was observed in rats and mice using a variety of behavioral paradigms, much like the present study. Modulation of anxiety-like behavioral responses has also been observed following i.c.v.…”

“…In addition, one explanation that must also be considered is that MCH signaling through its cognate receptor may act in a trophic manner to promote development of the serotonergic circuitry necessary for normal anxiety-like behaviors. However, in light of studies concluding that acute administration of a specific MCHR1 antagonist reduces anxiety-like behavior (Borowsky et al, 2002;Chaki et al, 2005), the trophic hypothesis of MCH signaling-induced effects on serotonergic transmission cannot solely explain the observed reduction in anxietylike behaviors.…”

“…Intracranial MCH administration has been shown to regulate response to novelty (Monzon et al, 2001;Kela et al, 2003) and learning and memory . In the most suggestive study to date, acute systemic administration of a selective MCHR1 receptor antagonist to rodents elicited both anxiolytic-and antidepressant-like effects (Borowsky et al, 2002;Chaki et al, 2005).…”