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 time course of action of the anxiolytic triazolobenzodiazepine, alprazolam, on the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of CRF neurons after acute and chronic administration. In addition, because many of the signs and symptoms observed in animals and humans after abrupt discontinuation of benzodiazepines resemble 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 between 0.5 and 3.0 h following acute injection. The half-life of alprazolam in rats is less than 1 h in both plasma and brain. Similarly, chronic (14 days) alprazolam administration also results in decreased CRF concentrations in the locus coeruleus. CRF concentrations return to control values 24 h after abrupt withdrawal. Moreover, abrupt alprazolam withdrawal results in increased plasma adrenocorticotrophic hormone and corticosterone concentrations and decreased anterior pituitary CRF receptor concentrations 24 h after drug discontinuation. These indices return to control values by 48 h postwithdrawal. These results support the hypothesis that both acute and chronic alprazolam administration alters CRF-containing neurons innervating the locus coeruleus. Additionally, abrupt alprazolam withdrawal profoundly activates the HPA axis.