OVERPRODUCTION OF CORTICOTROPIN-RELEASING FACTOR IN TRANSGENIC MICE -A GENETIC MODEL OF ANXIOGENIC BEHAVIOR

Corticotropin-releasing factor (CRF) is released in response to variou s stressors and regulates adrenocorticotropin secretion and glucocorti coid production. In addition to its endocrine functions, CRF acts as a neuromodulator in extrahypothalamic systems and has been shown to pla y a role in behavioral responses to stress. CRF overproduction has bee n implicated in affective disorders such as depression and anorexia ne rvosa. A transgenic mouse model of CRF overproduction has been develop ed in order to examine the endocrine and behavioral effects of chronic CRF excess. CRF transgenic animals exhibit endocrine abnormalities in volving the hypothalamic-pituitary-adrenal axis such as elevated plasm a levels of ACTH and glucocorticoids. The present series of experiment s tested the hypothesis that chronic overproduction of CRF throughout the life-span of these animals may lead to an anxiogenic behavioral st ate. CRF transgenic mice and normal littermate controls were tested by measuring locomotor activity in a novel environment and through the u se of an elevated plus-maze as indices of anxiety. CRF transgenic anim als exhibited an increase in anxiogenic behavior, an effect known to o ccur following central administration of CRF in mice and rats. Injecti on of the CRF antagonist or-helical CRF 9-41 into the lateral cerebral ventricles reversed the anxiogenic state observed in the CRF transgen ics. This finding supports the possibility that central CRF overproduc tion may mediate the anxiogenic behavior exhibited in this animal mode l. Thus, CRF transgenic mice represent a genetic model of CRF overprod uction that provides a valuable tool for investigating the long-term e ffects of CRF excess and dysregulation in the CNS.