Cellular responses to nicotinic receptor activation are decreased after prolonged exposure to galantamine in human neuroblastoma cells

J Barik, F Dajas-Bailador, S Wonnacott

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

1 In this study, we have examined cellular responses of neuroblastoma SH-SY5Y cells after chronic treatment with galantamine, a drug used to treat Alzheimer's disease that has a dual mechanism of action: inhibition of acetylcholinesterase and allosteric potentiation of nicotinic acetylcholine receptors ( nAChR). Acute experiments confirmed that maximum potentiation of nicotinic responses occurs at 1 mu M galantamine; hence this concentration was chosen for chronic treatment. 2 Exposure to 1 mM galantamine for 4 days decreased Ca2+ responses (by 19.8 +/- 3.6%) or [H-3] noradrenaline ([H-3] NA) release (by 23.9 +/- 3.3%) elicited by acute application of nicotine. KCl-evoked increases in intracellular Ca2+ were also inhibited by 10.0 +/- 1.9% after 4 days' treatment with galantamine. These diminished responses are consistent with the downregulation of downstream cellular processes. 3 Ca2+ responses evoked by activation of muscarinic acetylcholine receptors were unaffected by chronic galantamine treatment. Exposure to the more potent acetylcholinesterase inhibitor rivastigmine (1 mu M) for 4 days failed to alter nicotine-, KCl-, or muscarinic receptor-evoked increases in intracellular Ca2+. These observations support the hypothesis that chronic galantamine exerts its effects through interaction with nAChR in this cell line. 4 Exposure to 10 mu M nicotine for 4 days produced decreases in acute nicotine-(18.0 +/- 3.5%) and KCl-evoked Ca2+ responses (10.6 +/- 2.5%) and nicotine-evoked [H-3] NA release (26.0 +/- 3.3%) that are comparable to the effects of a corresponding exposure to galantamine. 5 Treatment with 1 mu M galantamine did not alter numbers of [H-3] epibatidine- binding sites in SH-SY5Y cells, in contrast to 62% upregulation of these sites in response to 10 mu M nicotine. 6 Thus, chronic galantamine acts at nAChR to decrease subsequent functional responses to acute stimulation with nicotine or KCl. This effect appears to be independent of the upregulation of nAChR-binding sites.
Original languageEnglish
Pages (from-to)1084-1092
Number of pages9
JournalBritish Journal of Pharmacology
Volume145
Issue number8
DOIs
Publication statusPublished - Aug 2005

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