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

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 31; no. 6; pp. 1135 - 1145
• Main Authors: Smith, Daniel G, Davis, Richard J, Rorick-Kehn, Linda, Morin, Michelle, Witkin, Jeffrey M, McKinzie, David L, Nomikos, George G, Gehlert, Donald R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2006
• Subjects: Acetylcholine - metabolism; Adrenocorticotropic Hormone - blood; Alprazolam - pharmacology; Animals; Anti-Anxiety Agents - pharmacology; Behavior, Animal - drug effects; Behavior, Animal - physiology; Body Temperature - drug effects; Brain Chemistry - drug effects; Brain Chemistry - physiology; Corticosterone - blood; Dose-Response Relationship, Drug; Hypothalamic Hormones - administration & dosage; Male; Maze Learning - drug effects; Maze Learning - physiology; Melanins - administration & dosage; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurosecretory Systems - drug effects; Neurosecretory Systems - metabolism; Pituitary Hormones - administration & dosage; Random Allocation; Receptors, Somatostatin - antagonists & inhibitors; Receptors, Somatostatin - deficiency; Receptors, Somatostatin - physiology; Stress, Physiological - metabolism; Stress, Physiological - physiopathology; Stress, Physiological - psychology
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/sj.npp.1300913

Repeated exposure to stressful conditions is linked to the etiology of affective disorders. The melanin-concentrating hormone-1 receptor (MCHR1) may be a novel mechanism that is involved in the modulation of stress responses and affective states. The role of MCHR1 in neuroendocrine, behavioral, and neurochemical stress, and anxiety-related responses was examined by monitoring the effects of melanin-concentrating hormone (MCH) and the selective MCHR1 antagonist, GW3430, in inbred C57Bl/6NTac and MCHR1-knockout (KO) and wild-type (WT) mice. Intracerebroventricular injection of MCH increased plasma corticosterone, and produced anxiety-related responses in the elevated plus maze. The selective MCHR1 antagonist, GW3430, blocked the neuroendocrine and behavioral effects of MCH and produced anxiolytic-like effects by itself in animal models of anxiety. Moreover, KO mice had an anxiolytic-like phenotype in behavioral models of anxiety, and GW3430 had anxiolytic-like effects in WT, but not KO mice. Lastly, stressor-evoked acetylcholine release within the prefrontal cortex of inbred and WT mice, but not KO mice, was blocked by GW3430. We show that MCH elicits anxiety-like responses and that the effects of a selective MCHR1 antagonist and the phenotype of KO mice are consistent with anxiolytic-like action. Distinct behavioral, physiological, and neurochemical stress, and anxiety-related responses were selectively modulated by the MCHR1, and these actions may involve corticolimbic regulation of stress responsivity and anxiety.