Circulating corticosterone alters the rate of neuropathological and behavioral changes induced by trimethyltin in rats.
When trimethyltin (TMT) is administered to rats, the plasma corticosterone concentration rises transiently 3 to 4 days later. We examined whether plasma corticosterone plays a causative role in the TMT-induced impairment of the hippocampus as assessed by pathological and behavioral tests. TMT-administered rats were supplementally treated with either adrenalectomy or metyrapone (twice daily for the first 7 days after TMT) in order to permanently deplete or transiently suppress circulating corticosterone. Loss of pyramidal cells in the CA1 and CA3 fields, mossy fiber sprouting, and impairment of spatial memory were observed after TMT intoxication. Adrenalectomy apparently aggravated both the hippocampal damage and the spatial memory impairment induced by TMT treatment. The TMT+metyrapone treatment groups exhibited a significant reduction in pyramidal cells in both the CA1 and the CA3 regions. However, the neuronal damage in CA1 was significantly different between the TMT and the TMT+metyrapone groups. Metyrapone significantly reduced the TMT-induced damage to pyramidal cells in CA1, but not CA3, and it also abolished mossy fiber sprouting. TMT-induced learning impairment and hyperactivity were alleviated by metyrapone treatment. It is thus concluded that both the high levels of corticosterone induced by TMT and the pathologically low levels of corticosterone induced by adrenalectomy will worsen the consequences of TMT.
Tsutsumi
S
S
Drug Safety Evaluation, Lead Optimization, Aventis Pharma Ltd., Kawagoe, Saitama 350-1165, Japan. shun.tsutsumi@aventis.com
Akaike
M
M
Arimitsu
H
H
Imai
H
H
Kato
N
N
D000315:Adrenalectomy; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002452:Cell Count; D003345:Corticosterone / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008797:Metyrapone / Q000494:pharmacology; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014298:Trimethyltin Compounds / Q000633:toxicity*
D004791:Enzyme Inhibitors; D014298:Trimethyltin Compounds; C037718:trimethyltin hydroxide; D003345:Corticosterone; D008797:Metyrapone