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 therefore determined whether adaptation in hypothalamic neurons underlies this decreased activity.


METHODS
Adult male rats were administered alcohol (4.5 g/kg intragastrically) or vehicle daily for three consecutive days and then were challenged with the vehicle or alcohol 7 days later. Levels of adrenocorticotropin hormone (ACTH) in the circulation, corticotropin-releasing factor (CRF), CRF receptors type 1 (CRFR1) and vasopressin (VP) transcripts in the paraventricular nucleus (PVN) of the hypothalamus, and CRF/VP peptide in the median eminence were measured.


RESULTS
Resting PVN levels of CRF, CRFR1, and VP were comparable in all animals 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 alcohol. 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.


CONCLUSIONS
Blunted neuronal activity of PVN CRF neurons may be responsible for the decreased ACTH response that we previously reported in rats that had been injected with alcohol several days earlier. In addition, and despite 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.
Lee
S
S
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, USA.
Schmidt
E D
ED
Tilders
F J
FJ
Rivier
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C
D000324:Adrenocorticotropic Hormone / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism; D014667:Vasopressins / Q000187:drug effects* / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D002492:Central Nervous System Depressants; D018019:Receptors, Corticotropin-Releasing Hormone; D014667:Vasopressins; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone