Stress hormone dysregulation at rest and after serotonergic stimulation among alcohol-dependent men with extended abstinence and controls

Background: Alcohol dependence has been associated with long-lasting alterations in limbic-hypohalamic-pituitary-adrenal (LHPA) axis and serotonin (5-hydroxytryptamine [5-HT]) function. Other conditions that are associated with alcoholism (cigarette smoking and antisocial personality disorder [ASPD]) have been linked with disturbances in these interrelated systems. We evaluated the stress hormone response to 5-HTergic stimulation in alcohol-dependent men with extended abstinence (average abstinence duration, 4.3 months) and controls to determine the relative contributions of alcoholism, cigarette smoking, and ASPD on baseline and provoked plasma cortisol and adrenocorticotropin hormone (ACTH) concentrations. Methods: One hundred nine alcohol-abstinent men with alcohol dependence (62%), habitual smoking (70%), and ASPD (43%) received D,L-fenfluramine (100 mg po) in a randomized, double-blind, placebo-controlled, crossover trial. The group of recovering alcohol-dependent individuals included abstinent primary alcohol-dependent men and alcohol-dependent men with ASPD, whereas the group of non-alcohol-dependent men comprised healthy controls and non-alcohol-dependent men with ASPD. plasma cortisol and ACTH levels were obtained at AM baseline and at half-hour intervals after drug administration. Subjective ratings of drug response and physiological measures were also obtained at baseline and every 30 min. Results: Abstinent alcohol-dependent men had significantly lower (approximately 20%) AM baseline plasma cortisol concentrations than non-alcohol-dependent men on both challenge days; however, no differences between the groups were observed with regard to resting AM plasma ACTH levels. After adjusting for these baseline differences. recovering alcohol-dependent men (area under curve = 35.6 +/- 37.4 [mug/dl] x min) had a twofold greater cortisol response to fenfluramine than non-alcohol-dependent men (area under curve = 17.5 +/- 32.5 [mug/dl] x min) (F = 5.1; df = 1,105; p < 0.03). The elevated cortisol response, which occurred primarily along the descending limb of the response carve, was paralleled by a nonsignificant statistical trend for alcohol-dependent men to also exhibit a greater ACTH response to fenfluramine at the 210-min (p < 0.07) and 240-min (p < 0.09) time points as compared with non-alcohol dependent men. Cigarette smoking and ASPD did not affect hormonal responses, nor could the groups' subjective ratings and physiological measures be distinguished. Conclusions: Alcohol-dependent men with extended abstinence differed from age- and race-matched non-alcohol-dependent men in resting AM and fenfluramine-induced plasma cortisol levels. This dysfunction in glucocorticoid homeostatic mechanisms was associated with alcoholism and not with smoking or ASPD. We also observed a nonsignificant statistical trend for plasma ACTH levels to be elevated among alcohol-dependent men along the descending limb of the response curve. Alcohol-dependent men seemed to have inherited or acquired damage to 5-HT-regulated LHPA axis function, the precise mechanisms and sites of which remain to be determined.