In light of the numerous but rather conflicting reports on the action of benzodiazepines upon the hypothalamo-hypophyseal-adrenal (HHA) axis activity, the effect of different doses of diazepam (0.1, 1.0 and 10.0 mg/kg) administered 15, 30, 60, 120 and 240 min before decapitation on plasma corticosterone level was studied in rats. While 0.1 mg/kg diazepam had no effect, 1.0 mg/kg diazepam decreased plasma corticosterone levels 30 and 60 min following drug administration. On the other hand, treatment with 10.0 mg/kg diazepam produced an increase in plasma corticosterone levels from 15-120 min following drug administration.

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Picrotoxin (1 mg/kg, i.p.) and a high dose of diazepam (10 mg/kg, i.p.) increased the concentration of plasma corticosterone in nonstressed rats. This effect of diazepam was unaffected by picrotoxin and bicuculline (GABA-A receptor blockers), atropine (a muscarinic receptor blocker), apomorphine (a dopamine receptor agonist), haloperidol (a dopamine receptor blocker) and yohimbine (an alpha-2-adrenergic receptor blocker); but was blocked by clonidine (an alpha-2-receptor agonist) and this effect of clonidine was reversed by yohimbine. Diazepam was unable to elevate plasma corticosterone levels in rats pretreated with dexamethasone. Clonidine and the GABA-B receptor agonist, baclofen, failed to affect the picrotoxin-induced rise of plasma corticosterone, but this rise was abolished by a low dose of diazepam (1 mg/kg). The results suggest that the diazepam-induced enhancement of ACTH release, presumably mediated by blockade of alpha-2-adrenergic receptors, is responsible for the observed increase of plasma corticosterone level in rats. On the other hand, the elevation of plasma corticosterone induced by picrotoxin appears to be mediated by GABA-A receptors.

Rats were treated with injections of diazepam (1 or 10 mg/kg) and stressed by restraint lasting 3 hours. This was performed once or, in animals immunized with sheep erythrocytes, repeatedly for 4 consecutive days. After repeated stress and/or diazepam treatment, the levels of brain noradrenalin decreased in all treated groups. Although both treatments (stress and diazepam) diminished the 5-hydroxytryptamine (5-HT)/5-hydroxyindoleacetic acid (5-HIAA) ratio, treatment with either dose of diazepam prevented the stress-induced fall of this ratio. The activity of hypothalamic glutamate decarboxylase, the enzyme taking part in GABA synthesis, was affected neither by the acute nor by repeated stress and/or diazepam treatment. The levels of plasma corticosterone were enhanced in all stressed rats, with and without drug. This finding was in accordance with the enhanced weights of adrenal glands in repeatedly stressed rats. The tendency to a corticosterone rise after repeated treatment with diazepam, 10 mg/kg, coincided with the enhanced weights of adrenal glands in these animals. The plaque-forming cell (PFC) response was reduced in all stressed animals and in animals treated with diazepam, 10 mg/kg. Accordingly, high doses of diazepam given repeatedly to rats are immunosuppressive, achieving this effect presumably by an enhancement of glucocorticoid secretion. Neither the low nor the high doses of diazepam affect the stress-induced enhancement of hypothalamohypophysial-adrenal axis activity and consecutive immunosuppression.