The effects of alprazolam on corticotropin-releasing factor neurons in the rat brain: implications for a role for CRF in the pathogenesis of anxiety disorders

Abstract

Considerable evidence indicates that corticotropin-releasing factor (CRF) is responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress. We have investigated the effects of the anxiolytic triazolobenzodiazepine, alprazolam, on the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of CRF neurons following acute and chronic administration. In addition, because many of the signs and symptoms observed in animals and humans following abrupt discontinuation of benzodiazepines resemble those of the stress response, we examined the effect of alprazolam withdrawal on CRF neurons and HPA axis activity. Alprazolam decreases CRF concentrations in the locus coeruleus 0.5-3.0 hours following acute injection. Similarly, chronic (14 days) alprazolam administration also results in decreased CRF concentrations in the locus coeruleus. CRF concentrations return to control values 24 hours following abrupt alprazolam withdrawal. Moreover, abrupt alprazolam withdrawal results in increased plasma ACTH and corticosterone concentrations and decreased anterior pituitary CRF receptor concentrations 24 hours following drug discontinuation. Thus, abrupt alprazolam withdrawal profoundly activates the HPA axis. These indices of HPA axis activity return to control values by 48 hours post-withdrawal. These actions of alprazolam on CRF neurons are opposite to those observed following acute or chronic stress. These results support the hypothesis that CRF-containing neurons innervating the locus coeruleus may be involved in the pathogenesis of anxiety, and in the actions of clinically efficacious anxiolytics.