EFFECT OF FLUMAZENIL ON BASAL AND NALOXONE-STIMULATED ACTH AND CORTISOL RELEASE IN HUMANS

1. Endogenous benzodiazepine receptor ligands are thought to influence the human hypo-thalamic-pituitary-adrenal (HPA) axis and naloxone, a known stimulator of adrenocorticotropic hormone (ACTH) release, is thought to act via release of hypothalamic corticotropin-releasing hormone. 2. The aim of the present study was to assess the influence of endogenous benzodiazepine-receptor ligands by administering flumazenil (Ro 15–1788), a benzodiazepine antagonist, and measuring ACTH and cortisol release, both basal and during naloxone-stimulation. 3. Nine normal volunteers in a placebo-controlled double-blind design were studied. Flumazenil (0.5 mg, i.v. bolus) was given 2 min before naloxone (125 μg/kg bodyweight, i.v. bolus) immunoreactive-adrenocorticotropic hormone (IR-ACTH) and cortisol levels were measured at frequent intervals from 60 min before to 120 min after naloxone injection. 4. Flumazenil had no effect on ACTH and cortisol release when given alone; flumazenil area under the ACTH/time curve (pmol/L.min) = -36.5 ± 63.5 compared with placebo = - 53.5± 31.8, flumazenil area under the cortisol/time curve (nmol/L.min x 10^?3) = - 2.4 ± 2.4 compared with placebo - 0.56 ± 1.4. Flumazenil did not change the ACTH and cortisol release achieved with naloxone; naloxone area under the ACTH/time curve (pmol/L. min) = 327.8 ± 61.7 compared with flumazenil/naloxone = 366.3 ± 88.1, naloxone area under the cortisol/time curve (nmol/L.minX 10^?3) = 12.2 ± 3.4 compared with naloxone/flumazenil = 10.5±2.1. 5. The authors conclude that flumazenil does not modify basal or stimulated ACTH and cortisol release in healthy humans. This would suggest that endogenous benzodiazepine-like ligands and the benzodiazepine/gamma-aminobutyric acid receptor complex do not tonically influence the hypothalamic-pituitary-adrenal axis.