Pharmacological characterization of a nicotinic autoreceptor in rat hippocampal synaptosomes |
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Authors: | G I Wilkie P Hutson J P Sullivan Dr S Wonnacott |
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Institution: | (1) School of Biology and Biochemistry, University of Bath, BA2 7AY Bath, UK;(2) Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, CM20 2QR Harlow, Essex, UK;(3) Abbott Laboratories, One Abbott Park Road, 60064-3500, Illinois |
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Abstract: | The modulation of 3H]ACh release by nicotinic compounds was studied in superfused rat hippocampal synaptosomes loaded with 3H]choline. (−)-Nicotine (0.1–10 μM) evoked a dose-dependent increase in 3H]ACh release; higher concentrations were less effective. Nicotine-evoked release was Ca2+-dependent, and blocked by the nicotinic antagonists dihydro-β-erythroidine, mecamylamine, and pempidine. The α7-selective
antagonist methyllycaconitine did not inhibit nicotine-evoked release when tested at 1 μM, although at 10 μM some attenuation
of the response was observed. Six agonists tested were equally efficacious in stimulating 3H]ACh release, as judged by the maximum responses, and gave the following EC50 values: (±)-epibatidine 0.12 μM; (+)-anatoxin-a 0.14 μM; (−)-nicotine 0.99 μM; (−)-cytisine 1.06 μM; ABT-418 2.6 μM; isoarecolone
43 μM. Each agonist generated a “bell-shaped” dose response curve, suggesting desensitisation at higher concentrations. This
is supported by analysis of repetitive stimulation with (−)-nicotine and (−)-cytisine: S2/S1 ratios declined sharply with
increasing concentration, whereas subsequent KCl-evoked release remained constant. These results are discussed in terms of
possible nicotinic receptor subtypes that might be present on hippocampal nerve terminals.
Special issue dedicated to Dr. Herman Bachelard. |
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Keywords: | Rat hippocampus nicotinic autoreceptor nicotinic receptor subtypes acetylcholine release epibatidine (+)-anatoxin-a (− )-nicotine (− )-cytisine ABT-418 |
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