title: The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice: involvement of dopaminergic systems.
abstract: Galantamine, a drug for Alzheimer's disease, is a novel cholinergic agent with a dual mode of action, which inhibits acetylcholinesterase and allosterically modulates nicotinic acetylcholine receptors (nAChRs), as a result stimulates catecholamine neurotransmission. In the present study, we investigated whether galantamine exerts cognitive improving effects through the allosteric modulation of nAChR in the intracerebroventricular beta amyloid (Abeta)(25-35)-injected animal model of Alzheimer's disease. Galantamine (3 mg/kg p.o.) significantly increased the extracellular dopamine release in the hippocampus of saline- and Abeta(25-35)-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Abeta(25-35)-injected mice, compared with saline-injected mice, could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting Abeta(25-35) induced cognitive impairment. Galantamine improved the Abeta(25-35)-induced cognitive impairment in the novel object recognition and fear-conditioning tasks. These improving effects of galantamine were blocked by the treatment with mecamylamine, SCH-23390, a dopamine-D1 receptor antagonist, and sulpiride, a dopamine-D2 receptor antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. This study provides the first in vivo evidence that galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of galantamine on the Abeta(25-35)-induced cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems, and the enhancement of dopamine release may be one of multiple mechanisms underlying the therapeutic benefit of galantamine.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wang
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Weiduo
authors.initials: W
authors.lastname: Chen
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism; D005239:Fear / Q000187:drug effects; D005702:Galantamine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage; D011978:Receptors, Nicotinic / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D018727:Muscarinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C074636:amyloid beta-protein (25-35); D005702:Galantamine; D012601:Scopolamine; D004298:Dopamine