Hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmineand arginine vasopressin administration: sex differences between major depressives and matched control subjects

Of heuristic value in understanding the neurochemistry of major depression is whether the hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivit y that occurs in this illness-can be related to putative neurotransmitter d ysfunction(s). Cholinergic neurotransmission stimulates hypothalamic cortic otropin releasing hormone (CRH) and arginine vasopressin (AVP) secretion, b oth of which stimulate pituitary corticotropin (ACTH) secretion, but whethe r the HPA axis in humans is activated only by doses of cholinergic agonists that produce noxious side effects remains controversial. To test the hypot hesis of increased cholinergic sensitivity in major depression, physostigmi ne (PHYSO), a reversible cholinesterase inhibitor, was administered to pati ents and control subjects at a dose that elevated plasma ACTH, cortisol, an d AVP concentrations but produced few or no side effects. Exogenous AVP als o was administered to determine if it would augment the effect of low-dose PHYSO on the HPA axis. Twelve premenopausal or estrogen-replaced female maj or depressives, 12 individually,matched: female control subjects, eight mal e major depressives, and eight matched male control subjects underwent four test sessions 5-7 days apart: PHYSO (8 mu g/kg IV), AVP (0.08 U/kg IM), PH YSO + AVP, and saline control. Serial blood samples were taken before and a fter pharmacologic challenge and analyzed for ACTH(1-39), cortisol, and AVP . Estradiol and testosterone were also measured at each test session. PHYSO (8 mu g/kg) significantly increased plasma ACTH, cortisol, and AVP, while producing no side effects in approximately half the subjects and predominan tly mild side effects in the other half. These hormone increases following PHYSO occurred primarily in the female depressives and the male control sub jects and:were not significantly related to the presence of absence of side effects. The greater the ACTH and AVP responses to PHYSO, the stronger the ir correlation, suggesting that AVP may have been acting as a secretagogue for ACTH. Administered AW significantly increased the secretion of ACTH in the patients and control subjects to a similar degree, and AW given after P HYSO did not augment the HPA axis response to a greater degree in the depre ssives than in the control subjects. Plasma estradiol and testosterone were within the normal range for all four groups of subjects and were not signi ficantly related to their HPA axis hormone responses. The study results sup port the hypothesis of heightened cholinergic sensitivity in premenopausal female, but not in male, patients with major depression. The low dose of PH YSO used may represent a useful paradigm for central cholinergic stimulatio n of the HPA axis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserv ed.