Role of Monoamines in Seizure Predisposition in the Genetically Epilepsy-Prone Rat

Abstract

The genetically epilepsy-prone rat (GEPR) is proving to be a useful model of the human epilepsies. Seizure predisposition in these animals is partially determined by widespread noradrenergic and serotonergic deficits in the brain. Drug-induced perturbations of these neurotransmitter systems cause predictable changes in seizure severity and/or susceptibility. Anticonvulsant effects occur in response to drugs or procedures which increase noradrenergic and/or serotonergic activity in the brain. In contrast, proconvulsant effects occur in response to interventions which substantially diminish either or both types of neurotransmission. Inhibition of norepinephrine synthesis alone does not exacerbate seizure activity in the GEPR. However, inhibition of synthesis either at the tyrosine hydroxylase step or the dopamine-beta-hydroxylase step prolongs seizure facilitating effects of drugs which inactivate norepinephrine storage vesicles. Synthesis inhibition also interacts with norepinephrine release produced by cold-induced stress or false transmitter-induced displacement to cause seizure facilitation. Some precursors to norepinephrine and serotonin are among the pharmacologic agents which produce anticonvulsant effects in the GEPR. The norepinephrine precursors, L-DOPA and dopamine, lose anticonvulsant effectiveness if conversion to norepinephrine is prohibited by synthesis inhibitors. Aspartame, an agent which can increase plasma phenylalanine and tyrosine concentrations, fails to facilitate or suppress sound-induced seizures in GEPRs even when doses are as high as 2000 mg/kg. Since in some circumstances phenylalanine can act as a tyrosine hydroxylase inhibitor and because tyrosine serves as the major dietary precursor to norepinephrine, an effect of large doses of aspartame on noradrenergic transmission might be hypothesized. However, our observations using the GEPR suggest that any possible effects of large aspartame doses on brain noradrenergic and serotonergic activity are functionally insignificant as determinants of seizure predisposition. These initial tests suggest that dietary aspartame has little or no risk of facilitating convulsions in subjects with seizure predisposition dependent upon innate noradrenergic and serotonergic deficits.