%0 Journal Article %A Donald R. Gehlert %A Jeffrey Cramer %A Michelle Morin %T The Effects of Subchronic CRH1 Receptor Antagonism on the Hypophyseal-Pituitary-Adrenal Axis of Rodents %D 2012 %R 10.1124/jpet.111.189753 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.111.189753 %X Corticotrophin-releasing hormone (CRH) is the major hypothalamic neuropeptide responsible for the stimulation of hypophyseal-pituitary-adrenal axis (HPAA) resulting in the synthesis and release of glucocorticoids from the adrenal cortex. Recently, we reported the discovery of the CRH1 receptor antagonist, 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) that has efficacy in preclinical models of stress-induced alcohol consumption. Since CRH1 is important in HPAA activation, we evaluated the effects of subchronic MTIP administration on rodent HPAA function. Initial studies established MTIP doses required for brain and pituitary CRH1 occupancy and associated with the inhibition of intracerebroventricular CRH on the HPAA in mice. Subsequently, rat basal plasma corticosterone (CORT) concentrations were measured hourly by radioimmunoassay for 24 hours following 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 hour 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 acute 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 following hyperinsulinemia may provide a surrogate strategy for a target occupancy biomarker. %U https://jpet.aspetjournals.org/content/jpet/early/2012/03/08/jpet.111.189753.full.pdf