Pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration in normal women and men

Animal studies indicate that central cholinergic neurotransmission stimulat es CRH secretion, but several human studies suggest that the hypothalamo-pi tuitary-adrenal cortical (HPA) axis may be activated only by doses of choli nergic agonists that produce noxious side effects and, by inference, a nons pecific stress response. Physostigmine (PHYSO), a reversible cholinesterase inhibitor, was administered to normal women and men at a dose that elevate d plasma ACTH(1-39), cortisol, and arginine vasopressin (AVP) concentration s but produced few or no side effects. Exogenous AVP also was administered alone and following PHYSO, to determine if it would augment the effect of P HYSO on the HPA axis. Fourteen normal women and 14 normal men matched to th e women on age and race underwent four test sessions 5 to 7 days apart: PHY SO (8 mu g/kg IV), AVP (0.08 U/kg IM), PHYSO plus AVP, and saline control. Serial blood samples taken before and after pharmacologic challenge were an alyzed for ACTH(1-39), cortisol, and AVP. PHYSO and AVP administration prod uced no side effects in about half the subjects and mild side effects in th e other half, with no significant female-male differences overall. There al so were no significant female-male differences in ACTH(1-39) or cortisol re sponses to AVP. In contrast, the men had significantly greater ACTH(1-39) r esponses to PHYSO administration than did the women. The endogenous AVP res ponse to PHYSO also was significantly greater in the men than in the women, and the ACTH(1-39) and AVP responses to PHYSO were significantly correlate d in the men (both = +0.70) but not in the women. None of the hormone respo nses wits significantly correlated with the presence or absence of side eff ects in either group of subjects. These results indicate a greater sensitiv ity of the HPA axis to low-close PHYSO in normal men than in normal women, which likely is mediated by increased secretion of AVP. The lack of differe nce in side effects between the two groups of subjects and the lack of sign ificant correlations between presence or absence of side effects and hormon e responses in either group suggest that the increased hormone responses in the men were due to increased responsibility of central cholinergic system s and not to a nonspecific stress response. (C) 1999 American College of Ne uropsychopharmacology. Published by Elsevier Science Inc.