INVOLVEMENT OF CORTICOTROPIN-RELEASING FACTOR IN CHRONIC STRESS REGULATION OF THE BRAIN NORADRENERGIC SYSTEM

Corticotropin-releasing factor (CRF) and norepinephrine (NE) mediate many hormonal, autonomic, and behavioral effects of acute stress, and it is possible that an interaction between these neurotransmitters could underlie neuronal adaptations in response to chronic stress. To test this hypothesis, the influence of chronically administered CRF and a specific CRF antagonist, alpha-helical CRF, on the induction of tyrosine hydroxylase, the rate-limiting enzyme in NE biosynthesis, was examined in the rat locus coeruleus (LC). We now report that administration of alpha-helical CRF specifically blocks the induction of tyrosine hydroxylase in response to a repeated intermittent stress paradigm involving foot shock and noise stress but has no effect on steady-state levels of the enzyme in nonstressed animals or on the induction of the enzyme in response to reserpine treatment. In addition, repeated administration of CRF alone for 5 days, like chronic stress, increases levels of tyrosine hydroxylase in LC. The results demonstrate that endogenous CRF is necessary for the induction of tyrosine hydroxylase in response to this stress paradigm and that exogenously administered CRF is sufficient for the regulation of this enzyme in nonstressed rats. These findings may prove important in elucidating mechanisms by which chronic stress triggers and sustains the biochemical alterations associated with some stress-related psychiatric disorders.