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)