EFFECTS OF NEFIRACETAM ON AMNESIA ANIMAL-MODELS WITH NEURONAL DYSFUNCTIONS

The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetami de (nefiracetam; DM-9384), on learning and memory in several amnesia a nimal models with neuronal dysfunctions were investigated. Nefiracetam improved scopolamine-, bicuculline-, picrotoxin-, ethanol-, chlordiaz epoxide- and cycloheximide-induced amnesia. Anti-amnesic action of nef iracetam on scopolamine model was antagonized by nifedipine and flunar izine, but not by diltiazem. Repeated administration of nefiracetam to AF64A-treated animals improved impairment of learning and memory as w ell as the alterations in cholinergic and monoaminergic neurotransmitt ers in the hippocampus. Basal forebrain (BF) lesioned rats induced by excitotoxin or by thermal coagulation showed impairment of learning ac companied by a marked reduction in choline acetyltransferase (ChAT) an d acetylcholine esterase activities. Nefiracetam improved the learning deficit of the BF-lesioned rats. Nefiracetam also improved the carbon monoxide-induced delayed and acute amnesia. Nefiracetam stimulated ac etylcholine release in the frontal cortex. Repeated administration of nefiracetam increased ChAT activity, gamma-aminobutyric acid (GABA) tu rnover and glutamic acid decarboxylase activity, and facilitated the N a+-dependent high-affinity GABA uptake. Nefiracetam activated the high voltage-activated (N/L-type) Ca2+ channel. The dose-response curves o f nefiracetam were bell-shaped in both behavioral and biochemical stud ies. Therefore, it is suggested that nefiracetam improves the dysfunct ion of cholinergic, GABAergic and/or monoaminergic neuronal function b y acting at Ca2+ channel and enhancing the release of neurotransmitter s, and modifies impairment of memory processes induced by drugs and hy poxia.