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 (Ab) 25À35 -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 Ab 25À35 -injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Ab 25À35 -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 Ab 25À35 induced cognitive impairment. Galantamine improved the Ab 25À35 -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 Ab 25À35 -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.

β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

“…Novel Object Recognition Test-The task was carried out according to previous publications (27,28). The experimental apparatus consisted of a Plexiglas open-field box (40 ϫ 40 ϫ 29 cm).…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. The allosteric properties of galantamine could directly lead to increased release of acetylcholine and activation of postsynaptic nAChRs (Samochocki et al, 2003) or act indirectly through its effects on the release of other neurotransmitters, especially glutamate and dopamine (Schilström et al, 2007;Wang et al, 2007). It has been demonstrated that amyloid- precursor protein (APP) is upregulated in a mouse model for Fragile X mental retardation (FXS) (Westmark et al, 2008) and two clinical studies have reported higher levels of APP in children with autism.…”

Characteristic Effects of Anti-dementia Drugs on Rat Sleep Patterns

“…Donepezil is a centrally acting selective, competitive, and reversible acetylcholinesterase inhibitor (3). Galantamine, a tertiary alkaloid extracted from the several species of Amaryllidacae, is an acetylcholinesterase inhibitor that also acts as an allosterically potentiating ligand on nicotinic acetylcholine receptors (4,5). On the other hand, memantine is well known to act as an antagonist on Nmethyl-D-aspartic acid (NMDA) receptors and has a protective effect against neuronal damage induced by excess glutamic acid (6).…”