Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to hCRH and AVP, but blunts the cortisol response to ACTH in humans

Alprazolam (AL), a benzodiazepine which activates gamma-amino butyrric acid (GABA)-ergic receptors, exerts a clear inhibitory effect on the activity of the hypothalamo-pituitary-adrenal (HPA) axis and is able to markedly reduce the ACTH response to metyrapone-induced inhibition of glucocorticoid feedback. It has been suggested that its inhibitory action could be regulated by CRH or AVP mediated mechanisms. However, the effect of benzodiazepines on the HPA response to CRH or AVP is contradictory. It has been shown that benzodiazepines have specific receptors on the adrenal gland but it is unclear if they mediate biological effects in humans. In order to further clarify the mechanisms underlying the inhibitory effect of benzodiazepine on HPA axis in humans, we studied the effect of AL (0.02 mg/kg po at -90 min) or placebo in 7 healthy young volunteers (7 female, age: 26-34 yr; wt: 50-58 kg, BMI 20-22 kg/m(2)) on: 1) the ACTH and cortisol responses to hCRH (2.0 mug/kg iv at 0 min) or AVP (0.17 U/kg im at 0 min); 2) the cortisol, aldosterone and DHEA responses to ACTH 1-24 (0.06 and 250 mug iv at 0 and 60 min, respectively). After placebo, the ACTH and cortisol responses to hCRH (peaks, mean SE: 29.8+/-4.4 pg/ml and 199.3+/-19.6 mug/l) were similar to those recorded after AVP (31.7+/-6.5 pg/ml and 164.8+/-18.0 mug/l); the cortisol response to 0.06 mug ACTH (190.4+/-11.8 mug/l) was similar to that recorded after hCRH and AVP but lower (p<0.01) than that after 250 μg ACTH (260.6±07.4 μg/l). AL did not modify the ACTH response to both hCRH (42.5±7.1 pg/ml) and AVP (33.3±2.7 pg/ml), which even showed a trend toward increase. AL also failed to significantly modify the cortisol response to both hCRH (156.3±12.7 μg/l) and AVP (119.4±14.5 μg/l), which, on the other hand, showed a trend toward decrease. The cortisol peaks after 0.06 μg ACTH were significantly reduced (p<0.02) by AL pre-treatment (115.0+/-7.7 mug/l) which, in turn, did not modify the cortisol response to the subsequent ACTH bolus (214.7+/-16.6 mug/l). The DHEA and aldosterone responses to all the ACTH doses were not significantly modified by AL. In conclusion, these data show that the HPA response to AVP as well as to hCRH is refractory to the inhibitory effect of AL which, in turn, blunts the cortisol response to low ACTH dose. These findings suggest that both CRH- and AVP-mediated mechanisms could underlie the CNS-mediated inhibitory effect of AL on HPA axis; in the meantime, these results suggest that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.