Effects of benzodiazepines receptor agonists on the hypothalamic-pituitary-adrenocortical axis

Previous studies have demonstrated that classical benzodiazepines decrease hypothalamic-pituitary-adrenocortical cortex (HPA) axis activity. Paradoxically, high doses of benzodiazepines also stimulate basal circulating corticosterone levels in some conditions. Because benzodiazepine agonists display little selectivity to any of the α subtypes of the γ-amino butyric acid (GABA)A receptor to which they bind, we propose that the unequivocal results are due to an α subtype-dependent modulation of the hypothalamic-pituitary-adrenocortical cortex axis output. To test this, basal hormonal output and induction of Fos in the hypothalamic paraventricular nucleus were measured after administration of various benzodiazepine ligands in mice. Zolpidem, a selective α1 subtype agonist, produced a very strong increase in plasma adrenocorticotropic hormone and corticosterone whereas the inverse agonist FG7142 induced a small rise in plasma corticosterone. More surprisingly, the non-selective full agonists diazepam and zopiclone induced a lower increase in circulating corticosterone than after zolpidem. In contrast, the α2,3,5-selective benzodiazepine agonist and α1 antagonist L-838,417 had no effect on corticosterone levels. Strong induction of Fos in the paraventricular nucleus was found in response to zolpidem, diazepam, and zopiclone, but not after L-838,417. Finally, pre-administration of L-838,417 prior to zolpidem strongly inhibited the effect of zolpidem on corticosterone. Likewise, the non-selective agonists diazepam and zopiclone at a dose that alone had no effect on corticosterone also inhibited the effect of zolpidem. Taken together, these results suggest that benzodiazepine ligands modulate the hypothalamic-pituitary-adrenocortical cortex axis through partly opposite mechanisms; and that the net effect is dependent on the composition of the GABAA receptor subunits to which they bind.