The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans

Alprazolam (ALP), a benzodiazepine that activates gamma-aminobutyric acid-e rgic receptors, inhibits the activity of hypothalamo-pituitary-adrenal (HPA ) axis, probably via inhibition of hypothalamic CRH and/or arginine vasopre ssin release. To further clarify the effects of ALP on the HPA axis in huma ns, in six normal young women (26-34 yr old) we studied the effects of 0.02 mg/kg ALP (administered orally at 0700 h) or placebo on ACTH, cortisol (F) , and 11-deoxycortisol (S) levels assayed after placebo or metyrapone (MET; 0.04 g/kg administered orally at 2300 h the night before). After placebo a dministration, ACTH, F, and S levels showed a progressive decrease from 070 0-1200 h (P < 0.03). At 0700 h, ACTH, F, and S levels before ALP overlapped with those after placebo. At 1200 h, ACTH, F, and S levels after ALP were lower than those after placebo (P < 0.03). MET pretreatment strongly increa sed ACTH (P < 0.03) and S (P < 0.02) while clearly inhibiting F (P < 0.03) levels at 0700 h. After MET, ACTH levels did not show any decrease up to 12 00 h; similarly, S levels persisted similar up to 1200 h, whereas F levels at 1200 h were significantly increased (P < 0.03). At 0700 h, MET-induced A CTH and F levels before ALP overlapped with those after MET alone. The MET- induced ACTH levels at 1200 h were markedly inhibited by ALP (P < 0.05). At 1200 h after MET and ALP, a clear reduction of S levels (P < 0.02) and an insignificant F reduction were also found. In conclusion, our present data show that ALP inhibits basal and, much more, metyrapone-induced corticotrop h secretion. These findings indicate that the inhibitory effect of central gamma-aminobutyric acid-ergic activation by ALP overrides the stimulatory e ffect of the MET-induced lack of negative F feedback on corticotroph secret ion. These results also point toward potential contraindication of ALP admi nistration in patients with suspected hypoadrenalism.