EFFECTS OF NEFIRACETAM (DM-9384), A PYRROLIDONE DERIVATIVE, ON BRAIN MONOAMINE SYSTEMS

The pyrrolidone cyclic gamma-aminobutyric acid (GABA) derivative nefir acetam [DM-9384; N-(2,6-dimethylphenyl)-2-(2-oxol-pyrrolidinyl )acetam ide] has been shown to enhance acquisition and ameliorate amnesia in d ifferent learning tasks in rodents. In the present study, the effects of nefiracetam on the brain monoamine systems were studied. Male, adul t Sprague-Dawley rats were treated with nefiracetam in single doses (0 , 1, 3, 10, 30 or 100 mg/kg, p.o.) and analyzed after 1 and 4 hr, or t reated by daily doses (0, 1, 3, 10 or 30 mg/kg, p.o.) for 2 weeks. In general, no or only weak effects were observed on tissue monoamine lev els, either following acute or 14 days treatment with nefiracetam. Acu te administration of intermediate doses of nefiracetam induced minor i ncreases in dopamine (DA) and homovanillic acid (HVA) tissue levels in the striatum, while hypothalamic 3,4-dihydroxyphenylacetic acid (DOPA C) decreased at 1 hr. Noradrenaline (NA) and serotonin (5-HT) levels i ncreased in some regions after higher doses of nefiracetam. Increases in 5-hydroxyindoleacetic acid (5-HIAA) were also seen at 4 hr, but onl y after the 3 mg/kg dose. Minor decreases of HVA and DOPAC levels were seen in some regions after treatment with various doses of nefiraceta m for 14 days, while an increase in 5-HT levels was observed occasiona lly. Using in vivo microdialysis in freely moving animals, no signific ant effects on extracellular levels of HVA, DOPAC and 5-HIAA in the st riatum or of HVA, DOPAC and NA levels in the dorsal hippocampus were s een after acute administration of nefiracetam. On the other hand, extr acellular hippocampal 5-HIAA levels decreased by 20% after the 1 and 3 mg/kg doses. Nefiracetam, in a concentration range of 1 nM to 10 mu M , did not affect the in vitro synaptosomal uptake of [H-3]NA and [H-3] 5-HT in the cortex or of [H-3]DA in the striatum. Taken together, nefi racetam appears to exert minor, regionally restricted and not dose-dep endent effects on the monoamine systems following either acute or repe ated administrations in normal rats. A direct or indirect, possibly GA BA-mediated, influence of nefiracetam may underlie the modest changes seen on monoamines. The cognitive-enhancing action of nefiracetam does not seem to be related to effects on presynaptic monoamine functions.