Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice.
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.
Smith
Daniel G
DG
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. dgs@lundbeck.com
Davis
Richard J
RJ
Rorick-Kehn
Linda
L
Morin
Michelle
M
Witkin
Jeffrey M
JM
McKinzie
David L
DL
Nomikos
George G
GG
Gehlert
Donald R
DR
D000109:Acetylcholine / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007028:Hypothalamic Hormones / Q000008:administration & dosage; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008543:Melanins / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism*; D010907:Pituitary Hormones / Q000008:administration & dosage; D011897:Random Allocation; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology
D014151:Anti-Anxiety Agents; D007028:Hypothalamic Hormones; C491209:Mchr1 protein, mouse; D008543:Melanins; D010907:Pituitary Hormones; D017481:Receptors, Somatostatin; C019463:melanin-concentrating hormone; D000324:Adrenocorticotropic Hormone; D000109:Acetylcholine; D003345:Corticosterone; D000525:Alprazolam