Rapid alteration of stress-induced hypothalamic-pituitary-adrenal hormone secretion in the rat: A comparison of glucocorticoids and cannabinoids

The hypothalamic-pituitary-adrenal (HPA) axis self-regulates through a glucocorticoid negative feedback mechanism that is stereotypically slow and long lasting. Rapid (seconds to minutes) glucocorticoid feedback, however, inhibits stress-induced adrenocorticotropic hormone (ACTH) secretion too quickly to result from classic transcriptional effects of the occupied glucocorticoid receptor. Cannabinoids may act as rapid intermediary messengers between glucocorticoids and HPA activation via retroactive inhibition of afferent glutamate stimulation of the corticotropin-releasing factor neurons in the paraventricular nucleus. We demonstrated fast feedback effects of GR stimulation and blockade and observed the effect of cannabinoid receptor (CB1) antagonist AM251 on HPA axis reactivity in vivo. Rats were injected intraperitoneally with varying doses of the specific GR agonist RU28362, the GR antagonist RU486, or AM251 2 min before restraint. Blood was collected at predetermined times and corticosterone and ACTH concentrations were measured. RU28362 blunted stress-induced ACTH secretion while RU486 and AM251 significantly increased stress-induced ACTH release 15 min after restraint onset. Next, we injected AM251 58 min before RU28362, 2 min before restraint, to determine if inhibition of ACTH by RU28362 was contingent on CB1 activation. Unexpectedly, CB1 blockade failed to prevent glucocorticoid negative feedback and instead enhanced it. These studies not only establish an in vivo fast feedback model but show that rapid glucococorticoid negative feedback is similarly altered by GR and CB1 blockade. Although the hormonal consequences of acute AM251 treatment were strikingly similar to those of RU486 treatment, we are unable to draw conclusions about the serial nature of the interaction between GR activation and CB release from these results.</.