Kainic acid-induced seizures: potentiation by alpha-methyl-p-tyrosine.
We have investigated the influence of central noradrenergic and dopaminergic systems on the susceptibility of rats to seizures in the kainic acid (KA)-model of epilepsy. In the dose range of 0.75 to 10 mg/kg s.c., KA dose-dependently induced characteristic behavioural changes. Partial depletion of noradrenaline (NA) and dopamine (DA) in the brain by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT; 250 mg/kg, i.p.) markedly potentiated KA-induced epileptic symptoms. A low dose of KA (1.5 mg/kg s.c.), which was ineffective in normal rats, triggered in AMPT-pretreated rats a high incidence of wet dog shakes (WDS) and a seizure activity (seizure rating: 3.17 +/- 0.31) which was comparable in degree to that resulting from 10 mg/kg KA in rats with normal catecholamine synthesis (seizure rating: 3.33 +/- 0.28). In AMPT-pretreated rats a higher dose of KA (10 mg/kg) further enhanced seizure activity and was associated with a mortality rate of up to 80%. Within 6.5 h after AMPT-pretreatment the levels of NA and DA in amygdala/pyriform cortex declined from 0.56 +/- 0.02 (control) to 0.23 +/- 0.01 ng/mg tissue and from 0.21 +/- 0.03 to 0.05 +/- 0.01 ng/mg tissue, respectively. At a dose of 1.5 mg/kg KA was ineffective on the levels of NA and DA in normal rats, but further reduced these levels in AMPT-pretreated rats to 0.08 +/- 0.02 and 0.020 +/- 0.004 ng/mg tissue, respectively. Induction of seizure activity and decline in NA and DA levels in amygdala/pyriform cortex after AMPT/KA (1.5 mg/kg) treatment was antagonized by the alpha-adrenoceptor agonist clonidine (0.1 mg/kg, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)
Institute of Biochemical Pharmacology, University of Vienna, Austria.
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Baran
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Hörtnagl
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Hornykiewicz
D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004827:Epilepsy / Q000139:chemically induced* / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D019805:alpha-Methyltyrosine
D008781:Methyltyrosines; D019805:alpha-Methyltyrosine; D003000:Clonidine; D003975:Diazepam; D007608:Kainic Acid; D004298:Dopamine; D009638:Norepinephrine