Tani Y, Saito K, Imoto M, Ohno T
Suntory Institute for Biomedical Research, Osaka, Japan.
Eur J Pharmacol. 1998 Jun 19;351(2):181-8. doi: 10.1016/s0014-2999(98)00314-8.
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.
采用体内微透析技术研究自由活动大鼠海马、额叶皮质和纹状体中烟碱受体介导的乙酰胆碱释放。腹腔注射（-）-尼古丁可增加海马和额叶皮质中乙酰胆碱的释放，但对纹状体无此作用。（-）-尼古丁呈现钟形剂量反应关系，在海马和额叶皮质中，最高剂量（5.0mg/kg腹腔注射）时反应减弱。在海马中，（-）-尼古丁（1.0mg/kg腹腔注射）诱导的乙酰胆碱释放增加可被中枢作用的烟碱受体通道阻滞剂美加明（1.0mg/kg腹腔注射）预处理所阻断，但六甲铵（5.0mg/kg腹腔注射）则无此作用，提示（-）-尼古丁的作用是由中枢烟碱受体介导的。据报道，（S）-3-甲基-5-（1-甲基-2-吡咯烷基）异恶唑（ABT-418，1.0和5.0mg/kg腹腔注射）是α4β2烟碱受体亚基的选择性激动剂，它也可增强海马中乙酰胆碱的释放，而对α7烟碱受体亚基具有高亲和力的3-（2,4-二甲氧基苄叉基）-阿那贝碱（GTS-21，1.0和5.0mg/kg腹腔注射）则无作用。从植物中分离得到的天然生物碱（-）-金雀花碱和（-）-洛贝林对海马中乙酰胆碱的释放影响很小。烟碱受体α4β2亚基的竞争性拮抗剂二氢-β-刺桐啶和含β2亚基烟碱受体的部分激动剂（-）-金雀花碱可抑制（-）-尼古丁诱导的海马中乙酰胆碱释放增加，而α7亚基的选择性拮抗剂甲基lycaconitine和含α3亚基烟碱受体的部分激动剂（-）-洛贝林则无此作用。这些结果表明，烟碱受体介导的乙酰胆碱释放在不同脑区的反应存在一定差异，且（-）-尼古丁诱导的大鼠海马中乙酰胆碱释放可能归因于α4β2烟碱受体亚基的激活。
