High doses of memantine (1-amino-3,5-dimethyladamantane) induce seizures in kindled but not in non-kindled rats

Abstract

Memantine (1-amino-3,5-dimethyladamantane) has previously been shown to attenuate or block chemically or electrically induced seizures in rodents at doses of 5-20 mg/kg i.p., suggesting that the drug might have potential utility in the treatment of seizures. In the present study, the effects of memantine were examined in amygdala-kindled and non-kindled rats. In fully kindled rats, i.e. a model of focal seizures with secondary generalization, memantine exerted no effects on seizure parameters at 5 mg/kg i.p., but reduced seizure severity and duration at 10 mg/kg. The threshold for induction of afterdischarges recorded from the amygdala was not altered after administration of 10 mg/kg. At 20 mg/kg, memantine induced spontaneous motor seizures in amygdala-kindled rats. No motor seizures were observed in non-kindled rats, but in both kindled and non-kindled animals memantine, 20 mg/kg, induced spikes in the electroencephalogram. Additional dose-dependent behavioural alterations observed after memantine included hyperactivity, ataxia and stereotypies, which may relate to the dopaminomimetic properties of the drug. The results demonstrate that kindled rats are more sensitive to central nervous system stimulating effects of memantine than non-kindled rats, which could relate to an impairment of inhibitory processes and/or alterations in synaptic transmission mediated by excitatory amino acids in the kindled brain.