CRF receptor regulation and sensitization of ACTH responses to acute ether stress during chronic intermittent immobilization stress

Abstract

The relationship between corticotropin releasing factor (CRF) receptors and pituitary-adrenal responses was determined after chronic intermittent immobilization (2.5 h restraint/day) to examine the hypothesis that CRF receptor regulation is involved in the sensitization of the pituitary-adrenocortical axis to novel stimuli during repeated stress. Following the 11-fold stimulation of ACTH secretion on the first day of restraint stress, a desensitization of the pituitary ACTH response to immobilization was observed over the next 9 days of chronic intermittent stress. In contrast, the magnitude of the restraint-stimulated release of corticosterone on the 2nd and 4th day of stress was similar to the day 1 adrenocortical response. Furthermore, the significant stimulation of corticosterone secretion by restraint stress persisted to the 16th day of immobilization ( P < 0.001), even though significant increases in plasma ACTH were absent. The concentration of anterior pituitary CRF receptors was unchanged after a single period of restraint; however, a down-regulation of anterior pituitary CRF receptors was observed following 4 days ( P < 0.001) and 10 days ( P < 0.005) of repeated immobilization stress. CRF receptors in the plfactory bulb wre unchanged following acute or chronic restraint stress, consistent with previous observations that brain CRF receptors are neither changed by adrenalectomy, glucocorticoid administration, nor 18–48 h of continuous restraint stress. The concentration of CRF receptors in the intermediate lobe of the pituitary also was not influenced by immobilization stress. Despite the desensitization of the ACTH response during repeated immobilization, a highly significant potentiation ( P < 0.001) ACTH release following 5 min of ether vapor was observed 24 h following 9 or 15 days of repeated restraint stress. Consequently, the loss of anterior pituitary CRF receptors cannot account for the sensitazation of the ACTH response to acute ether exposure following chronic immobilization stress. The data support the hypothesis that the increased pituitary corticotroph responses to novel stressful stimuli during chronic stress involves the ‘facilitation’ of stimulatory inputs to CRF-releasing neurons in the hypothalamus and the integrative actions of CRF and other ACTH regulators at the post-CRF receptor level.