Richard S. Jaeckle

Stimulation of the pituitary-adrenal axis with arginine vasopressin in patients with depression.

The ACTH response to arginine vasopressin was the same in patients with depression while cortisol response was significantly greater in patients with depression when compared to the control population. These findings are consistent with the hypothesis that vasopressin corticotroph receptors are not downregulated in depression and that there is increased adrenal responsiveness in patients with depression to endogenous ACTH.

Imipramine effect on hypothalamic-pituitary-adrenal axis response to hypoglycemia

Six control subjects underwent an insulin tolerance test before and after the administration of therapeutic doses of imipramine hydrochloride for 10 days to investigate effects of tricyclic antidepressants on hypothalamic-pituitary-adrenal axis response to hypoglycemia. The mean steady-state tricyclic blood level was 141 (SD = 66) ng/ml. Baseline levels of glucose, cortisol, and adrenocorticotropic hormone (ACTH) were not affected by the administration of imipramine. After administration of imipramine for 10 days, subjects uniformly had a significantly lower glucose nadir than before its administration (before imipramine: mean = 32 mg/dl; SD = 5; after imipramine: mean = 24 mg/dl; SD = 6). There was no difference in ACTH or cortisol response before and after the administration of imipramine. These findings suggest that imipramine hydrochloride increases sensitivity to the hypoglycemic effects of insulin, but does not alter the counterregulatory response of ACTH and cortisol.

MULTIPLE STEROID HORMONE LEVELS IN DEPRESSED PATIENTS AND NORMAL CONTROLS BEFORE AND AFTER EXOGENOUS ACTH

Forty depressed patients and 36 age- and sex-matched controls were given 250 micrograms ACTH1-24 by IV bolus. Plasma steroid hormone levels were measured prior to and 60 min after ACTH administration. The depressed patients had significantly greater cortisol (F), 11-deoxycortisol (S), androstenedione (AD), and 17 alpha-hydroxyprogesterone (17 alpha-OHP) responses (delta; p less than 0.05) and a marginally greater 11 beta-hydroxyandrostenedione (11 beta-OHAD) response (delta; p = 0.091) than the controls. There was no significant difference in the corticosterone (B) response between the two groups. With the exception of 11 beta-OHAD, all the steroid hormones were significantly negatively correlated with age in the controls, but only S and AD marginally demonstrated this relationship in the depressed patients. F, S, AD, 17 alpha-OHP, and B, but not 11 beta-OHAD, were significantly positively correlated with each other in the controls, but only F was significantly correlated with AD in the depressed patients. These data suggest that the hypercortisolemia found in some depressed patients involves increased precursor and metabolite levels both at baseline and in response to exogenous ACTH, compared to controls. Furthermore, variability in these precursors is greater in depressed patients, and their relationship to age is lost. These findings are consistent with the hypothesis that adrenal products other than cortisol also could be related to affective symptoms.

Stable adrenocorticotropin-stimulated 11-β-hydroxylase activity but loss of age-related changes in patients with hypercortisolemia

Eleven-beta-hydroxylase activity was measured before and after acute adrenocorticotrophic hormone (ACTH) stimulation in 28 controls, 25 depressed Dexamethasone Suppression Test (DST) suppressors, 13 DST nonsuppressor patients, and 8 patients with Cushings syndrome to investigate changes in states of cortisol hypersecretion. Eleven-beta-hydroxylase activity was equivalent among groups both before and after stimulation. Such 11-beta-hydroxylase stability, however, resulted in higher cortisol and 11-deoxycortisol poststimulation levels in both depressed DST nonsuppressors and Cushings patients than in controls. Basal 11-beta-hydroxylase activity is positively correlated and 11-deoxycortisol is negatively correlated with age in controls and DST suppressors, but not in the patients tested with evidence of cortisol hypersecretion. These findings suggest that in vivo basal 11-beta-hydroxylase activity rises gradually with age, but does not rise after acute administration of exogenous ACTH. The age relationship is lost in states of cortisol hypersecretion, but the lack of response to acute exogenous ACTH is not affected.

Chronic stress supersensitizes rats to the inhibition of locomotion produced by arecoline

Chronic inescapable footshock and swim stress supersensitize a hypothalamic muscarinic mechanism which regulates core body temperature. We studied the inhibitory effects of arecoline, a muscarinic agonist, on locomotion in rats before and after chronic swim stress in order to examine the effects of stress on an extra-hypothalamic muscarinic mechanism. We counted crossings in an open field during the days before and after six days of twice-daily swim stress (8 minutes/session at 12C). We first examined the effects of eight doses of ip arecoline (0.01 to 2.0 mg/kg) and normal saline (N = 6 to 8 rats/group) on crossings before and after chronic stress. Doses greater than 0.25 mg/kg inhibited pre-stress crossings relative to saline and did not potentiate the inhibition of locomotion post-stress. The 0.125 mg/kg dose reduced crossings post-stress relative to saline. We reexamined the effects of the 0.125 mg/kg dose saline (N = 20 rats/group) on crossings before and after six days of swim stress. Chronic stress potentiated arecoline-induced inhibition of locomotion. Our results suggest that chronic uncontrollable stressors may supersensitize an extra-hypothalamic muscarinic mechanism involved in the stress response and the pathophysiology of stress-related disease such as major depression.