Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission

Nefiracetam (1-10 mu M), a nootropic (or cognition-enhancing) agent, persis tently potentiated currents through Torpedo acetylcholine (ACh) receptors e xpressed in Xenopus oocytes as a result of interacting with a protein kinas e C pathway and the ensuing protein kinase C phosphorylation of the recepto rs. A similar effect was found in neuronal nicotinic ACh receptors (alpha 4 beta 2 and alpha 7). In contrast, the other nootropic agents such as pirac etam and aniracetam had no potentiating action on the receptors. A sustaine d enhancement in the activity of nicotinic ACh receptors induced by nefirac etam caused a marked increase in the glutamate release, leading to a longte rm potentiation-like facilitation of hippocampal synaptic transmissions. On e of the consistent neuropathologic features of the Alzheimer brain is a lo ss of nicotinic ACh receptors. This fact, together with the results of our study, raises the possibility that the loss of nicotinic ACh receptors may be a key factor in the decline of cognitive function observed in Alzheimer disease and that agents targeting neuronal nicotinic ACh receptors like nef iracetam could, therefore, be of great therapeutic importance.