During anesthetic-induced activation of hypothalamic pituitary adrenal axis, blood-borne steroids fail to contribute to the anesthetic effect.
Anesthetic doses of ethanol (100 mmol/kg p.o.), chloral hydrate (2 mmol/kg i.p.), and urethane (9 mmol/kg i.p.) induce sharp and sustained (6- to 10-fold) dose-dependent increase in rat brain pregnenolone and progesterone content. In contrast, other general anesthetics such as ketamine (0.7 mmol/kg i.p.) and pentobarbital (0.2 mmol/kg i.p.), and the sedative/hypnotic clonazepam (17 mumol/kg i.p.) decrease brain pregnenolone and progesterone content. The increase in brain pregnenolone and progesterone content fails to occur if ethanol, chloral hydrate, and urethane are administered to hypophysectomized-adrenalectomized rats suggesting that the increase of brain steroids requires the hypophysis and probably originates in peripheral tissues and not in brain. The administration to hypophysectomized rats of 5 IU/kg of ACTH produces a brain pregnenolone and progesterone accumulation by an extent comparable to that elicited by anesthetic doses of ethanol, chloral hydrate, or urethane in intact animals. However, the increase in brain pregnenolone and progesterone content induced by ACTH is devoid of anesthetic or sedative effects and does not appear to change central GABAergic tone. In fact, ACTH, unlike allopregnanolone and allodeoxicorticosterone, failed to delay the onset of isoniazid-induced seizures, to reduce the fear of novelty in the elevated plus maze test as inferred by the increase in the number of entries or the time spent in the open arm. Thus, the data suggest that blood-borne steroids cannot function as precursors of brain neurosteroid modulators acting on GABAA receptor.
Fidia-Georgetown Institute for the Neurosciences, Georgetown University School of Medicine, Washington, DC 20007.
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Korneyev
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Costa
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Guidotti
D000311:Adrenal Glands / Q000187:drug effects* / Q000502:physiology; D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000758:Anesthesia; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002697:Chloral Hydrate / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D007016:Hypophysectomy; D007031:Hypothalamus / Q000187:drug effects* / Q000502:physiology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects* / Q000502:physiology; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000097:blood*
D000777:Anesthetics; D013256:Steroids; D000431:Ethanol; D002697:Chloral Hydrate; D011374:Progesterone; D002998:Clonazepam; D007649:Ketamine; D000324:Adrenocorticotropic Hormone; D010424:Pentobarbital