EFFECT OF SODIUM VALPROATE ON NALOXONE-STIMULATED ACTH AND CORTISOL RELEASE IN HUMANS

1. Gamma-aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone , stimulates the release of CRH, and so of ACTH and cortisol, while al prazolam, an indirect GABA(A) agonist, blocks naloxone-induced ACTH an d cortisol secretion. Sodium valproate (SV) inhibits ACTH release in r esponse to CRH, metyrapone and substance P. We hypothesized that, if t his action is GABA(A)-mediated, SV should also inhibit naloxone-stimul ated ACTH release. 2. We studied five healthy volunteers in randomized , double-blind, placebo-controlled afternoon studies with SV 400 mg, g iven 180 min before i.v. naloxone 125 mu g/kg bodyweight. Plasma conce ntrations of ACTH, cortisol and SV were measured at intervals during t he experiments. 3. SV had no effect on the mean integrated ACTH and co rtisol responses to naloxone; ACTH: 165+/-21 versus 284+/-40 pmol.min per L, P=0.08; cortisol: 10.5+/-1.9 versus 12.8+/-1.2 nmol.min per L(- 3), P=0.14, placebo/nal versus SV/nal respectively. Basal ACTH and cor tisol levels were also not significantly altered by SV (P>0.30). Mean SV levels were not significantly different between SV/nal and SV/place bo studies (P>0.50). 4. In conclusion, SV had no effect on naloxone-in duced ACTH and cortisol release in normal humans at the dose and plasm a drug concentrations studied. This contrasts with the potent inhibito ry effect of alprazolam, and suggests that the effect of SV on the hum an hypothalamic-pituitary-adrenal axis may not be through a GABA(A)-me diated mechanism. Alternatively, higher plasma SV levels or more susta ined exposure to SV may be necessary to inhibit hypothalamic secretion of CRH.