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 (Aβ)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 Aβ25−35-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Aβ25−35-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 Aβ25−35 induced cognitive impairment. Galantamine improved the Aβ25−35-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 Aβ25−35-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.
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Acknowledgements
We are grateful to the Janssen Pharmaceutical KK for donating galantamine. This work was supported, in part, by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (14370031) (15922139) (16922036) (17390018), for Scientific Research on Priority Areas on ‘Elucidation of glia-neuron network mediated information processing systems’ from Ministry of Education, Culture, Sports, Science and Technology (16047214), for Funds from Integrated Molecular Medicine for Neuronal and Neoplastic Disorders (21st Century COE program), for the Japan Brain Foundation, for the Mitsubishi Pharma Research Foundation and, for an SRF Grant for Biomedical Research.
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Wang, D., Noda, Y., Zhou, Y. et al. 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. Neuropsychopharmacol 32, 1261–1271 (2007). https://doi.org/10.1038/sj.npp.1301256
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DOI: https://doi.org/10.1038/sj.npp.1301256
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