Restraint-stress-induced changes in exploratory behavior appear to be mediated by norepinephrine-stimulated release of CRF.

Exploratory behavior, measured by the time an animal spends investigating objects in a novel environment, has been shown to be sensitive to prior exposure of the animal to stressors. Using this paradigm, it was demonstrated previously that both corticotropin-releasing factor (CRF) and the alpha 2-adrenoreceptor antagonist, idazoxan, elicited stress-like decreases in exploratory behavior. Because an activation of cerebral noradrenergic systems is observed during stress, following intracerebroventricular (i.c.v.) administration of CRF, or following peripheral administration of idazoxan, the involvement of noradrenergic systems in the behavioral effect of restraint and CRF was examined. Inhibition of norepinephrine (NE) release using the alpha 2-agonist clonidine (25 micrograms/kg, i.p.) or the noradrenergic-selective neurotoxin DSP-4 antagonized the restraint-induced decrease in exploratory behavior. The combination of these 2 treatments completely prevented this effect of restraint. The alpha 1-receptor antagonist prazosin (200 micrograms/kg) also prevented the behavioral effect of restraint, whereas the alpha 1-agonist phenylephrine (50 or 100 ng, i.c.v.) decreased exploratory behavior. None of these treatments consistently altered locomotor activity as measured by the number of entries into the different compartments or the number of rears. These results implicate noradrenergic systems in the stress-related changes in this behavior, consistent with our parallel measures on the production of NE catabolites. Thus, both CRF and noradrenergic systems appear to be involved in the effect of restraint on exploratory behavior in this task. Neither DSP-4 nor prazosin had any effect on the CRF-induced decrease in exploratory behavior. However, the CRF antagonist alpha-helical CRF (20 micrograms, i.c.v.) reversed the decrease in exploratory behavior induced by phenylephrine. The most likely explanation is that the 2 systems act in tandem such that noradrenergic systems regulate the release of brain CRF via an alpha 1-adrenoreceptor. This arrangement parallels that involved in the release of hypothalamic CRF to activate the pituitary-adrenal axis. The implications of these results for research on stress-related behaviors and for the etiology of depression are discussed.