Pharmacological characterization of nicotinic receptor-mediated acetylcholine release in rat brain--an in vivo microdialysis study.
In vivo microdialysis was used to investigate nicotinic receptor-mediated acetylcholine release in the hippocampus, frontal cortex, and striatum of freely moving rats. Intraperitoneal administration of (-)-nicotine increased the release of acetylcholine in the hippocampus and frontal cortex but not in the striatum. (-)-Nicotine exhibited a bell-shaped dose-response relationship, and showed attenuation of response at the highest dose (5.0 mg/kg i.p.) in both the hippocampus and frontal cortex. In the hippocampus, (-)-nicotine (1.0 mg/kg i.p.)-induced increase of acetylcholine release was blocked by pretreatment with the centrally acting nicotinic receptor channel blocker, mecamylamine (1.0 mg/kg i.p.), but not by hexamethonium (5.0 mg/kg i.p.), suggesting that the effects of (-)-nicotine were mediated by the central nicotinic receptor. (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418, 1.0 and 5.0 mg/kg i.p.), reported to be a selective agonist for alpha4beta2 nicotinic receptor subunits, also enhanced the release of acetylcholine in the hippocampus, while 3-(2,4-dimethoxybenzlidene)-anabaseine (GTS-21, 1.0 and 5.0 mg/kg i.p.), which has high affinity for the alpha7 nicotinic receptor subunit, was without effect. The natural alkaloids isolated from plants, (-)-cytisine and (-)-lobeline, had little effect on acetylcholine release from the hippocampus. A competitive antagonist for alpha4beta2 subunits of the nicotinic receptor, dihydro-beta-erythroidine, and a partial agonist for the beta2 subunit-containing nicotinic receptor, (-)-cytisine, inhibited (-)-nicotine-induced increase of acetylcholine release from the hippocampus, whereas a selective antagonist for the alpha7 subunit, methyllycaconitine, and a partial agonist for the alpha3 subunit-containing nicotinic receptor, (-)-lobeline, did not. These results indicate that there are certain differences among brain regions in the response of nicotinic receptor-mediated acetylcholine release and that (-)-nicotine-induced acetylcholine release in the rat hippocampus may be attributed to activation of the alpha4beta2 nicotinic receptor subunits.
Suntory Institute for Biomedical Research, Osaka, Japan. yoshihiro_tani@suntory.co.jp
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Tani
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Saito
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Imoto
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Ohno
D000109:Acetylcholine / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001392:Azocines; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003367:Cotinine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008024:Ligands; D008120:Lobeline / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017551:Microdialysis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011807:Quinolizines; D051381:Rats; D011916:Rats, Inbred F344; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D001392:Azocines; D003367:Cotinine; D008024:Ligands; D008120:Lobeline; D008464:Mecamylamine; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011807:Quinolizines; D011978:Receptors, Nicotinic; C004712:cytisine; D000093843:Quinolizidine Alkaloids