Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems

In view of the substantial preclinical evidence that supports a seminal rol e of central corticotropin-releasing factor (CRF) neuronal systems in the p hysiology and pathophysiology of stress and anxiety, it is reasonable to su ggest that the anxiolytic properties of benzodiazepines are mediated, at le ast in part, via regulation of CRFergic function. To begin to test this com plex hypothesis, we examined the effects of acute and chronic administratio n of the triazolobenzodiazepine agonist alprazolam on CRF peptide concentra tions, receptor-binding density, and mRNA expression in the CNS. Additional ly, we measured mRNA expression for urocortin, a recently discovered neurop eptide that is generally considered to be a second endogenous ligand for CR F receptors. Both acute and chronic alprazolam administration was found to decrease CRF concentrations within the locus coeruleus. Furthermore, chroni c alprazolam decreased basal activity of the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central nucleus of the amygdala, and CRF1 mRNA expression and receptor binding in the basolateral amygdala. In marke d contrast, urocortin mRNA expression in the Edinger-Westphal nucleus and C RF2A receptor binding in the lateral septum and ventromedial hypothalamus w ere increased. Similar findings of an inverse relationship between the CRF1 and CRF2A receptor systems have been reported in an anxiety model based on adverse early-life experience, suggesting the intriguing possibility that CRF neuronal systems may be comprised of two separate, but interrelated, su bdivisions that can be coordinately and inversely regulated by stress, anxi ety, or anxiolytic drugs.