title: Effects of corticotropin-releasing factor 1 receptor antagonism on the hypothalamic-pituitary-adrenal axis of rodents.
abstract: Corticotropin-releasing factor (CRF) is the major hypothalamic neuropeptide responsible for stimulation of the hypothalamic-pituitary-adrenal axis (HPAA), resulting in the synthesis and release of glucocorticoids from the adrenal cortex. In a recent study, we reported the discovery of the CRF1 receptor antagonist, 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP), which has efficacy in preclinical models of stress-induced alcohol consumption. Because CRF1 is important in HPAA activation, we evaluated the effects of MTIP administration on rodent HPAA function. Initial studies established the MTIP doses required for brain and pituitary CRF1 occupancy and those associated with the inhibition of intracerebroventricular CRF on the HPAA in mice. Then, rat basal plasma corticosterone (CORT) concentrations were measured hourly by radioimmunoassay for 24 h after three daily doses of MTIP or vehicle. In these studies, the early phase of the nocturnal CORT surge was reduced; however, the area under the CORT curve was identical for the 24-h period. In subsequent studies, increases in plasma CORT due to direct pharmacological manipulation of the HPAA axis or by stressors were evaluated after MTIP treatment in mice. MTIP attenuated CORT responses generated by immediate bolus administration of insulin or ethanol; however, MTIP did not affect activation of the HPAA by other stressors and pharmacological agents. Therefore, MTIP can modulate basal HPAA activity during the CORT surge and reduced activation after a select number of stressors but does not produce a lasting suppression of basal CORT. The ability of MTIP to modulate plasma CORT after hyperinsulinemia may provide a surrogate strategy for a target occupancy biomarker.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. gehlert_donald_r@lilly.com
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cramer
authors.forename: S Michelle
authors.initials: SM
authors.lastname: Morin
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D029845:Amphibian Proteins / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D003345:Corticosterone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036361:Peptide Hormones / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: C518650:3-(4-chloro-2-morpholin-4-ylthiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo(1,2-b)pyridazine; D029845:Amphibian Proteins; D036361:Peptide Hormones; D011724:Pyridazines; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D000099052:CRF Receptor, Type 1; C025727:sauvagine; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone