THE EFFECT OF DESIPRAMINE ON BASAL AND NALOXONE-STIMULATED CORTISOL SECRETION IN HUMANS - INTERACTION OF 2 DRUGS ACTING ON NORADRENERGIC CONTROL OF ADRENOCORTICOTROPIN SECRETION

Desipramine (DMI), a tricyclic antidepressant and norepinephrine (NE) reuptake blocker, is reported to induce ACTH and cortisol release acut ely in humans, probably by facilitating central NE neurotransmission. Tricyclic antidepressant therapy, including DMI, normalizes the ACTH a nd cortisol hypersecretion that often accompanies depression. The mech anism of hypothalamic-pituitary-adrenal (HPA) axis inhibition by DMI i n humans is unknown. In rats, DMI reduces the activity of the locus ce ruleus, a major source of NE innervation of the hypothalamic paraventr icular nucleus, the site of CRH neurons. Naloxone induces ACTH and cor tisol release in humans through a noradrenergic-mediated mechanism and a probable consequent stimulation of hypothalamic CRH release. To stu dy the interaction of these drugs on NE neurotransmission and, hence, HPA axis activity in humans, we administered DMI alone and with naloxo ne in a randomized, double blind, placebo-controlled protocol in eight healthy male volunteers. DMI (75 mg, orally) was given 180 min before naloxone (125 mu g/kg BSV, iv). Plasma ACTH and cortisol were measure d at frequent intervals from 60 min before to 120 min after naloxone t reatment. Plasma cortisol levels were 77% higher 180 min after DMI com pared to those after placebo treatment(287 +/- 17 vs. 162 +/- 14 nmol/ L; P = 0.000005). DMI reduced the naloxone-induced rise in cortisol (P = 0.02), but there was no change in the integrated cortisol response. The increase in basal plasma ACTH levels after DMI treatment did not reach statistical significance. DMI significantly increased systolic b lood pressure and heart rate consistent with an effect on the noradren ergic control of the cardiovascular system. In summary, DMI increased basal cortisol levels consistent with facilitation of NE neurotransmis sion and, hence, hypothalamic CRH release. However, DMI had no enhanci ng effect on naloxone-induced cortisol release. This contrasts with th e synergy observed when non-antidepressant agents that increase NE neu rotransmission are given with naloxone to humans. DMI increases glucoc orticoid feedback sensitivity in the rat HPA axis after several weeks through up-regulation of central corticosteroid receptors. However, th is slowly developing effect is unlikely to occur during these acute st udies. The effect of DMI on naloxone-induced cortisol release is consi stent with an inhibitory effect on central noradrenergic control of AC TH release, perhaps at the locus ceruleus. This is the first human stu dy to suggest an inhibitory effect of DMI on central noradrenergic con trol of ACTH release.