Cellular mechanisms underlying cognition-enhancing actions of nefiracetam (DM-9384)

We have studied cellular mechanisms underlying cognition-enhancing actions of nefiracetam (DM-9384), a newly developed cognitive enhancer, by biochemical experiments on cholinergic and GABAergic transmissions as well as electrophysiological experiments on neuronal Ca2+ channels. In behavioral experiments in rats, nefiracetam (3 mg/kg) ameliorated amnesia induced by basal forebrain (BF) lesion or treatment of scopolamine. Biochemical experiments revealed that nefiracetam increased uptake and release of transmitters in both cholinergic and GABAergic systems in rat brain. In electrophysiological studies, nefiracetam (1 microM) increased long-lasting (N/L-type) Ca2+ channel currents in NG108-15 cells. The nefiracetam action on Ca2+ channels was blocked by pertussis toxin (PTX). The results suggest that nefiracetam improves impaired memory by facilitating cholinergic and GABAergic transmissions in the brain. It is further suggested that PTX-sensitive G-proteins and Ca2+ channels associated with these G-proteins are responsible for the action of nefiracetam on neurotransmission.