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Journal of Neuroscience, Vol 14, 2579-2584, Copyright © 1994 by Society for Neuroscience
Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior
MP Stenzel-Poore, SC Heinrichs, S Rivest, GF Koob and WW Vale
Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California.
Corticotropin-releasing factor (CRF) is released in response to various
stressors and regulates adrenocorticotropin secretion and glucocorticoid
production. In addition to its endocrine functions, CRF acts as a
neuromodulator in extra-hypothalamic systems and has been shown to play a
role in behavioral responses to stress. CRF overproduction has been
implicated in affective disorders such as depression and anorexia nervosa.
A transgenic mouse model of CRF overproduction has been developed in order
to examine the endocrine and behavioral effects of chronic CRF excess. CRF
transgenic animals exhibit endocrine abnormalities involving the
hypothalamic-pituitary- adrenal axis such as elevated plasma levels of ACTH
and glucocorticoids. The present series of experiments tested the
hypothesis that chronic overproduction of CRF throughout the life-span of
these animals may lead to an anxiogenic behavioral state. CRF transgenic
mice and normal littermate controls were tested by measuring locomotor
activity in a novel environment and through the use of an elevated
plus-maze as indices of anxiety. CRF transgenic animals exhibited an
increase in anxiogenic behavior, an effect known to occur following central
administration of CRF in mice and rats. Injection of the CRF antagonist
alpha-helical CRF 9-41 into the lateral cerebral ventricles reversed the
anxiogenic state observed in the CRF transgenics. This finding supports the
possibility that central CRF overproduction may mediate the anxiogenic
behavior exhibited in this animal model. Thus, CRF transgenic mice
represent a genetic model of CRF overproduction that provides a valuable
tool for investigating the long-term effects of CRF excess and
dysregulation in the CNS.
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