Role of glucocorticoids in the cholinergic degeneration in rat hippocampus induced by ethylcholine aziridinium (AF64A).
Glucocorticoids potentiate hippocampal damage induced by various noxious insults in vivo and in vitro and are implicated in age-related loss of neurons in the hippocampus of various species. The cholinergic innervation of the hippocampus appears to be especially prone to the endangering effect of glucocorticoids, since corticosterone, like acute stress or ACTH, induces a rapid activation of the cholinergic septo-hippocampal pathway. We now report the influence of glucocorticoids on the degeneration of this pathway induced by the cholinergic neurotoxin ethylcholine aziridinium (AF64A). The toxic effect of a submaximal dose of AF64A on cholinergic neurons was evaluated in rats during exposure to glucocorticoids or vehicle as well as in adrenalectomized or sham-operated rats. Daily treatment with either corticosterone or dexamethasone, starting 7 d before the bilateral intracerebroventricular injection of AF64A (1 nmol/ventricle), significantly increased the AF64A-induced loss of ChAT activity in the whole hippocampus, whereas bilateral adrenalectomy 7 d prior to AF64A-injection attenuated the effect of AF64A. Short-term exposure to corticosterone starting 24 hr before AF64A was as effective as the 7 d pretreatment. Dexamethasone exacerbated the AF64A-induced cholinergic lesion in the hippocampal subregions CA1, CA3, and dentate gyrus, and adrenalectomy protected all subregions against the action of AF64A. Along the longitudinal axis of the hippocampus a comparable influence was seen in the dorsal and ventral parts. The subregional pattern in the response to glucocorticoid suggests the involvement of mineralocorticoid type I receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Hörtnagl
H
H
Institute of Biochemical Pharmacology, University of Vienna, Austria.
Berger
M L
ML
Havelec
L
L
Hornykiewicz
O
O
D000109:Acetylcholine / Q000378:metabolism*; D000315:Adrenalectomy; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000633:toxicity*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003345:Corticosterone / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D009638:Norepinephrine / Q000378:metabolism; D009928:Organ Specificity; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001388:Aziridines; D009498:Neurotoxins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D005680:gamma-Aminobutyric Acid; D003907:Dexamethasone; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D002794:Choline; D000109:Acetylcholine; D003345:Corticosterone; D009638:Norepinephrine