Strategies Targeting Alzheimer-type DementiaPresynaptic Nicotinic Acetylcholine Receptors As a Functional Target of Nefiracetam in Inducing a Long-lasting Facilitation of Hippocampal NeurotransmissionNishizaki, Tomoyuki; Matsuoka, Toshiyuki; Nomura, Tamotsu; Kondoh, Takeshi*; Watabe, Shigeo†; Shiotani, Tadashi†; Yoshii, Mitsunobu‡Author Information Departments of Physiology and *Neurosurgery, Kobe University School of Medicine, Chuo-ku, Kobe; †Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Kitakasai, Edogawa-ku; and ‡Department of Neurophysiology, Tokyo Institute of Psychiatry, Setagaya-ku, Tokyo, Japan Address correspondence and reprint requests to Dr. Tomoyuki Nishizaki, Department of Physiology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Alzheimer Disease and Associated Disorders: 2000 - Volume 14 - Issue 1 - p S82-S94 Buy Abstract Nefiracetam (1–10 μM), a nootropic (or cognition-enhancing) agent, persistently potentiated currents through Torpedo acetylcholine (ACh) receptors expressed in Xenopus oocytes as a result of interacting with a protein kinase C pathway and the ensuing protein kinase C phosphorylation of the receptors. A similar effect was found in neuronal nicotinic ACh receptors (α4β2 and α7). In contrast, the other nootropic agents such as piracetam and aniracetam had no potentiating action on the receptors. A sustained enhancement in the activity of nicotinic ACh receptors induced by nefiracetam caused a marked increase in the glutamate release, leading to a long-term potentiation-like facilitation of hippocampal synaptic transmissions. One of the consistent neuropathologic features of the Alzheimer brain is a loss 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 nefiracetam could, therefore, be of great therapeutic importance. © 2000 Lippincott Williams & Wilkins, Inc.