Effect of chronic administration of a CRF(1) receptor antagonist, CRA1000, on locomotor activity and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is involved in the regulation of stress responses. The actions of CRF in the brain are mediated through two distinct CRF receptor subtypes, CRF(1) and CRF(2) receptors. In the present study, we examined the effects in rat of chronic administration of a nonpeptidic CRF(1) receptor-selective antagonist, CRA1000, 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine), on locomotor activity, feeding behavior and the hypothalamic-pituitary-adrenal axis. Chronic CRA1000 treatment significantly decreased locomotor activity in the dark phase of the diurnal cycle. However, chronic CRA1000 treatment showed no effect on food and water intake, or on body weight. After a 10-day period of CRA1000 treatment, plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in basal conditions and under immobilization stress were no different from those in rats treated with vehicle. However, CRA1000 administered 2 h before immobilization stress significantly reduced ACTH and corticosterone responses to stress with no effect on basal ACTH and corticosterone concentrations. These results suggest that CRF(1) receptors are involved in the regulation of locomotor activity during the dark period, but are not involved in the regulation of feeding behavior under non-stressful conditions. Furthermore, the results suggest that a 10-day treatment with CRA1000 does not affect hypothalamic-pituitary-adrenal axis activity either under basal conditions or after acute stress.