1991 Fiscal Year Final Research Report Summary
Studies on acute toxicity of nicotine and aging
| Project/Area Number |
01570112
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
General pharmacology
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| Research Institution | Nara Medical University |
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Principal Investigator |
NAKASHIMA Toshikatsu Nara Med. Univ., Dept. Pharmacol., Professor, 医学部, 教授 (00075045)
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| Project Period (FY) |
1989 – 1991
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| Keywords | Nicotine / Aging / Acute toxicity / Kinetics / Convulsion / Lethal dose / Nervous amino acid / Brain nicotine levels |
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| Research Abstract |
We studied on acute toxicity of nicotine and aging, using 6 week-old and 2 year-old male Wistar rats. Concerning the mortality in 15 min. after a intraperitoneal injection (ip) of nicotine (24.5 mg/kg), 6 week-old rat was 42.9%, and 2 year-old, 77.8%. The onset of tremor, clonic-convulsion and tonic-convulsion after nicotine (iP) presented time-dependent and dosedependent. The duration of convulsion after nicotine (5 mg/kg, iP) in 2 year-old rats was longer than these after in 6 week-old. Hepatic nicotine oxidase activity, cytochrome P-450 in microsomes and flavin monoxygenase activity of 2 year-old rats were about half of these in liver of 6 week-old. Serum corticcisterone. monoamine levels in hypothalamus, hippocampus and striatum decreased accord with aging. Dopamine, DOPAC and 5-HT levels in hippocampus increased with nicotine (24.5 mg/kg, iP). Serum corticosterone and monoamine levels in alive rats after nicotine (24.5 mg/kg, iP) were higher than these in lethal. The 50% of convul
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sion dose after intracerebroventricular injection (icv) of nicotine was 58.5 ug/side in 6 week-old, and the 50% of lethal dose, 477.6 ug/side. These toxicity of nicotine (icv) increased dose-dependently' Mecamylamine antagonized dose-dependently these toxicity of nicotine. The administration (icv) of phenobarbital, diazepam, MK-801 and SCH-23390 depressed these toxic actions after nicotine (iP). These results suggested as follow : Acute toxicity of nicotine are affected high by pharmacokinetics. The depression of metabolizing enzyme activity and excretion leads to increase of nicotine concentration in serum and brain. Acute death of nicotine is respiratory suppression due to central convulsion. GABA and excitatory amino acid depressed the convulsion.
The protein of nicotinic acetylcholine receptor (nAChR) purified high in whole rat brain. The protein band of 53 kdal and of 80 kdal are beta2 subunit and alpha4 subunit of nACliR respectively. Application of cAMP-dependent protein kinase specifically phosphorylated only alpha4 subunit of nAChR. Serine residues in alpha4 subunit were exclusively phosphorylated. Less
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