Neuroactive steroid adaptations following chronic alcohol consumption

Neuroactive steroids contribute to alcohol sensitivity and regulate stress homeostasis in the central nervous system. The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathology of alcoholism. A blunted HPA axis response has been found in both drinking and abstinent alcohol-dependent patients. We compared HPA axis regulation of the neuroactive steroid deoxycorticosterone (DOC) in cynomolgus monkeys and humans. Pharmacological challenges with naloxone, saline, corticotrophin releasing factor (CRF), dexamethasone, and adrenocorticotropic hormone (ACTH) were conducted in monkeys prior to and following 12 months of voluntary alcohol drinking, and in healthy humans vs. 1-month abstinent alcohol-dependent patients. DOC levels were measured in plasma samples by radioimmunoassay. Long-term alcohol self-administration increased basal DOC levels (+244%, p<0.001) in monkeys. DOC responses to CRF and dexamethasone challenges were blunted, responses to ACTH challenge were enhanced and responses to naloxone challenge were not altered by long-term alcohol exposure. In humans, basal DOC levels and DOC responses to HPA axis challenges did not differ in healthy subjects vs. abstinent alcohol-dependent patients, except for a delayed time to peak DOC response following CRF challenge in the alcohol-dependent patients. These data suggest different adaptations in HPA-mediated DOC responses in monkeys vs. humans. This is likely due to different alcohol exposure parameters (actively drinking state vs. 1-month abstinence) or to the induction procedure of alcohol self-administration in monkeys. Studies are underway to investigate if neuroactive steroid adaptations in monkeys are influenced by abstinence following long-term alcohol consumption. Supported by AA13515, AA13510 and AA11570.