Both acute central administration of exogenous, and stress-induced release of endogenous corticotropin-releasing factor result in electrophysiological activation of the noradrenergic neurons constituting the locus coeruleus. The present experiments were designed to examine whether single (1) or repeated (8) intracerebroventricular pretreatment with exogenous corticotropin-releasing factor would alter locus coeruleus electrophysiological responsivity to subsequent corticotropin-releasing factor challenge in rats. A single corticotropin-releasing factor (3 microg) pretreatment significantly attenuated challenge-induced locus coeruleus activation 24 and 72, but no 96 h later, while a single vehicle pretreatment had no significant effect on the response to subsequent challenge at any pretreatment-to-test interval. Repeated pretreatment with either corticotropin-releasing factor or vehicle completely attenuated locus coeruleus response to challenge 24 h after the final pretreatment. Seventy-two hours after the last vehicle pretreatment, challenge resulted in a significant increase in locus coeruleus activity, though the response was less than in naive controls. Challenge continued to produce no effect on locus coeruleus activity in repeated corticotropin-releasing factor-pretreated rats at this (72 h) time point. One week (168 h) after the cessation of repeated pretreatment, challenge resulted in a significant increase in locus coeruleus activity which was equal to that of naive controls in vehicle-pretreated rats, but reduced by comparison to controls in corticotropin-releasing factor-pretreated rats. Basal discharge rates of locus coeruleus neurons 24 h after the last repeated corticotropin-releasing factor pretreatment were significantly less than in naive controls. Thus, the failure of challenge to increase neuronal activity in these rats was not due to a "ceiling" effect caused by elevated tonic discharge rate. Repeated vehicle pretreatment produced a functional change similar to that produced by exogenous corticotropin-releasing factor administration. One hypothesis is that repeated vehicle pretreatment was stressful and caused the repeated release of endogenous corticotropin-releasing factor. This hypothesis was tested by determining whether locus coeruleus neurons remained responsive to challenge following repeated administration of a corticotropin-releasing factor antagonist. Thus, the effect if repeated pretreatment with the antagonist, [D-Phe, Nle, Calpha MeLeu]CRF was also examined. Challenge resulted ina significant increase in discharge rate 24 h after the final antagonist pretreatment, providing support for the hypothesis. Additionally, in rats repeatedly pretreated with vehicle, carbachol challenge induced an increase in locus coeruleus activity equal to that induced in naive controls. These results indicate that prior exposure to corticotropin-releasing factor, or the repeated mild stress of vehicle infusions, reduces locus coeruleus responsiveness to corticotropin-releasing factor, and reveal that the relationship between these two neurotransmitter systems is modifiable. This altered relationship may contribute to stress-related affective disorders in which both systems have been implicated.