Diazepam increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity by a cyclic AMP-dependent mechanism.

1. Previous studies in this laboratory have shown that diazepam behaves as a phosphodiesterase 4 (PDE 4) inhibitor. It has been reported that PDE-4 inhibitors activate the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat. In the present study we have examined whether activation of the cyclic AMP-dependent protein kinase (PKA) is involved in the effect of diazepam on basal HPA axis activity. 2. Acute systemic administration of diazepam (10 mg kg(-1) i.p.) was found to increase the basal HPA axis activity, increasing the plasma concentrations of corticotrophin (ACTH) and corticosterone 30 min post injection. Diazepam also elevated cyclic AMP content of the hypothalamus. 3. Pretreatment of the animals with dexamethasone (1 mg kg(-1) s.c.) for 3 days completely abolished the effect of diazepam on HPA axis activity. 4. The antagonists of central and peripheral benzodiazepine receptors, flumazenil (10 mg kg(-1) i.p.) and PK 11195 (5 mg kg(-1) i.p.) did not affect the diazepam induced increase of HPA axis activity nor did they have an effect per se. 5. The increase in ACTH and corticosterone levels was significantly reduced by the cyclic AMP-dependent protein kinase (PKA) inhibitor, H-89, given either subcutaneously (5 mg kg(-1) s.c.) or intracerebroventricularly (i.c.v.; 28 microg in 10 microl). 6. The results indicate that diazepam can stimulate basal HPA axis activity in the rat by a cyclic AMP-dependent PKA mediated pathway.