Effects of Sodium Valproate and Diazepam on Beta-Endorphin, Beta-Lipotropin and Cortisol Secretion Induced by Hypoglycemic Stress in Humans

Abstract

Evidence that γ-aminobutyric acid (GABA) and benzodiazepine receptors play a role in the inhibition of ACTH-cortisol secretion in humans has until now been drawn only from data indicating that sodium valproate, a GABA mimetic, and diazepam, a benzodiazepine, decrease hypothalamus-pituitary-adrenal (HPA) axis secretion in patients affected by pathological hypersecretion of the axis. Therefore, the present study investigated the effects, in the same healthy subjects, of sodium valproate or diazepam, on both basal and stress-stimulated concentrations of β-endorphin (β-EP), β-lipotropin (β-LPH) and cortisol. A single maximal dose of sodium valproate (400 mg) or diazepam (10 mg) did not significantly modify basal concentrations of β-EP, β-LPH and cortisol. On the other hand, in the same subjects, pretreatment with sodium valproate (20 mg × 3) or diazepam (10 mg × 2) blocked the increases in these hormones produced by hypoglycemic stress in all patients tested (p< 0.01 vs. placebo at 45, 60 and 90 min after insulin injection), without affecting the decrease in blood glucose levels. The present data show that sodium valproate and diazepam inhibit stress-induced β-EP, β-LPH and cortisol secretion in humans, suggesting that endogenous GABA and benzodiazepine receptors participate in physiological mechanisms regulating the activity of the HPA axis.

Inhibitory effect of diazepam on the activity of the hypothalamic-pituitary-adrenal axis in female rats

“…Our results also agree with the data obtained in humans, which show suppressed cortisol secretion after benzodiazepine treatment in healthy subjects (Gram et al, 1984;Christensen et al, 1992;Schuckit et al, 1992), in panic disorders (Lopez et al, 1990) and in insulin-induced hypoglycemia (Petraglia et al, 1986;Ambrosi et al, 1986). The presented data confirm the conclusions of De Souza (1990), who summarized the neuroendocrine effects of benzodiazepines and postulated that benzodiazepines alter HPA function probably through inhibition of the hypothalamic release of CRH, although some other options (an action on brain monoamines or a direct effect on peripheral-type benzodiazepine receptors) were also discussed.…”

Cortisol response to diazepam: its relationship to age, dose, duration of treatment, and presence of generalized anxiety disorder

“…These effects have been most convincingly demonstrated with high potency BZPs, such as alprazolam. In contrast, low potency BZPs, such as diazepam, have generally been shown to influence HPA axis activity only in individuals experiencing some degree of stress (Hommer et al 1986;Petraglia et al 1986;RoyByrne et al 1988RoyByrne et al , 1991De Souza 1990;Vongsavan et al 1990a).…”

In Vitroandin VivoEffects of the Triazolobenzodiazepine Alprazolam on Hypothalamic Pituitary-Adrenal Function: Pharmacological and Clinical Implications*

“…ALPRAZOLAM AND HYPOTHALAMIC-PITUITARY- ADRENAL FUNCTION 1463 In contrast to CRH, which seems to function as one of the principal activating agents in the central nervous system, the 7-aminobutyric acid (GABA) system is the principal inhibitory system in the brain (14). In this regard, GABA has many effects antithetical to those of CRH, including suppression of pituitary-adrenal function (15)(16)(17)(18)(19)(20)(21)(22) and the locus ceruleus firing rate (23)(24)(25), and inhibition of basal arousal, anxiety, and responsiveness to threatening situations (26).…”