Effect of repeated exposure to alcohol on the response of the hypothalamic-pituitary-adrenal axis of the rat: I. Role of changes in hypothalamic neuronal activity

Background: Prior (3-12 days) injection of alcohol significantly blunts the response of the hypothalamic-pituitary-adrenal (HPA) axis to a second drug challenge without measurably altering responses to other stressors. We the refore determined whether adaptation in hypothalamic neurons underlies this decreased activity. Methods: Adult male rats were administered alcohol (4.5 g/kg intragastrical ly) or vehicle daily for three consecutive days and then were challenged wi th the vehicle or alcohol 7 days later. Levels of adrenocorticotropin hormo ne (ACTH) in the circulation, corticotropin-releasing factor (CRF), CRF rec eptors type 1 (CRFR1) and vasopressin (VP) transcripts in the paraventricul ar nucleus (PVN) of the hypothalamus, and CRF/VP peptide in the median emin ence were measured. Results: Resting PVN levels of CRF, CRFR1, and VP were comparable in all an imals on day 7 of recovery, whereas CRF and VP stores in the external zone of the median eminence were decreased in animals previously exposed to alco hol. After the acute alcohol challenge on day 7, rats previously exposed to the drug exhibited a significant (p < 0.01) dampening of their PVN CRF and CRFR1, but not VP neuronal response, compared with vehicle-pretreated rats . Conclusion: Blunted neuronal activity of PVN CRF neurons may be responsible for the decreased ACTH response that we previously reported in rats that h ad been injected with alcohol several days earlier. In addition, and despit e comparable PVN VP transcript levels, the lower levels of this peptide in the median eminence also may participate in the blunted ACTH response that we observed.