ABSTRACT
Melanin-concentrating hormone (MCH) is an orexigenic and dipsogenic neuropeptide that has been reported to mediate acute behavioral and neuroendocrine stress-related responses via MCH(1) receptor activation in rodents. The purpose of the present investigation was to use the MCH(1) receptor antagonist SNAP 94847 (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperidin-4-yl}-4-methyl-phenyl)-isobutyramide) to determine the effects of MCH(1) receptor blockade on MCH-evoked adrenocorticotropic hormone (ACTH) release, chronic mild stress-induced anhedonia, stress-induced hyperthermia and forced swim stress-induced immobility. The appropriate dose range for testing SNAP 94847 was determined by measuring MCH-evoked water drinking. The corresponding occupancy of MCH(1) receptors in rat striatum was also measured across a broad dose range. Orally administered (p.o.) SNAP 94847 (1-10 mg/kg) corresponds to 30-60% occupancy at MCH(1) receptors and significantly blocks water drinking induced by the intracerebroventricular (i.c.v.) injection of MCH. MCH (i.c.v.) significantly elevates plasma levels of ACTH in rats, and SNAP 94847 (2.5 mg/kg, p.o.) blocks MCH-evoked ACTH release. Using the chronic mild stress paradigm, we show that repeated daily exposure to environmental stressors for 5 weeks significantly suppresses sucrose intake in rats, and that SNAP 94847 (1 mg/kg, BID) for 1-5 weeks restores baseline sucrose intake. Moreover, a single administration of SNAP 94847 attenuates stress-induced hyperthermia and the behavioral effects of forced swim stress with minimal effective doses of 2.5 and 30 mg/kg (p.o.), respectively. The regulation of ACTH release and reversal of the effects of chronic and acute stress by SNAP 94847 are suggestive of a role for MCH(1) receptor blockade in the treatment of disorders characterized by high allostatic load.
Subject(s)
Hypothalamo-Hypophyseal System/physiology , Piperidines/pharmacology , Pituitary-Adrenal System/physiology , Stress, Physiological/physiology , Administration, Oral , Adrenocorticotropic Hormone/blood , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Drinking/drug effects , Drinking/physiology , Hypothalamo-Hypophyseal System/drug effects , Injections, Intravenous , Injections, Intraventricular , Male , Motor Activity/drug effects , Motor Activity/physiology , Piperidines/administration & dosage , Pituitary-Adrenal System/drug effects , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Pituitary Hormone/physiology , Stress, Physiological/drug effectsABSTRACT
Inflammation is now recognized as an overwhelming burden to the healthcare status of our population and the underlying basis of a significant number of diseases. The elderly generally bear the burden of morbidity and mortality, which may be reflective of elevated markers of inflammation resulting from decades of lifestyle choices. Lower cancer rates are associated with diets high in fiber, fruits, vegetables, and tea. AD and PD may be prevented or treated with aggressive vitamin E, curcumin, acetylcarnitine, and catechin supplementation. Cardiovascular disease, metabolic syndrome, hypertension, diabetes, and hyperlipidemia may be ameliorated by treating the underlying cause: inflammation caused by visceral adipose tissue. It is no longer appropriate to allow our dietary habits to contribute to the morbidity and mortality of the majority of humans. Although there is much more to understand, we have enough information presently to make the necessary changes in our lifestyles to significantly affect the inflammatory process and potentially live longer, healthier lives, with fewer burdens to an overburdened and failing medical system.
