Warpman U, Zhang X, Nordberg A
Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
J Pharmacol Exp Ther. 1996 May;277(2):917-22.
The effects of tacrine (THA) on extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were investigated in the striatum of freely moving rats, using a microdialysis technique in which tacrine was administered locally via the microdialysis membrane. THA in concentrations of 10(-8) to 10(-5) M, significantly elevated the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, whereas a significantly increased content of extracellular DA was observed at higher concentrations of THA (10(-3) to 10(-2) M). Local administration of the muscarinic antagonist atropine (10(-6) M) or the nicotinic antagonist mecamylamine (10(-5) M) both prevented the effects of THA on DA and its metabolites. In vitro receptor binding studies showed that THA displaced the binding of muscarinic antagonists [3H]pirenzepine (IC50, 2.1 +/- 0.4 microM) and [3H]AFDX 384 (IC50, 3.4 +/- 0.2 microM) equally in striatal tissue, suggesting that THA binds with equal affinity to M1 and M2 muscarinic receptor subtypes. THA showed a 20-fold lower affinity to high-affinity nicotinic receptors compared with muscarinic receptors when determined by [3H]cytisine competition curves. The study indicates that THA enhances monoamine neurotransmission in the rat striatum, probably via an interaction with both muscarinic and nicotinic heteroreceptors.
采用微透析技术，通过微透析膜局部给予他克林（THA），研究其对自由活动大鼠纹状体中多巴胺（DA）、3,4 - 二羟基苯乙酸、高香草酸和5 - 羟基吲哚乙酸细胞外浓度的影响。浓度为10^(-8)至10^(-5)M的THA显著提高了DA代谢物3,4 - 二羟基苯乙酸和高香草酸的水平，而在较高浓度的THA（10^(-3)至10^(-2)M）下观察到细胞外DA含量显著增加。局部给予毒蕈碱拮抗剂阿托品（10^(-6)M）或烟碱拮抗剂美加明（10^(-5)M）均可阻止THA对DA及其代谢物的影响。体外受体结合研究表明，THA在纹状体组织中同等程度地取代了毒蕈碱拮抗剂[3H]哌仑西平（IC50，2.1±0.4μM）和[3H]AFDX 384（IC50，3.4±0.2μM）的结合，表明THA与M1和M2毒蕈碱受体亚型具有同等亲和力。通过[3H]金雀花碱竞争曲线测定，与毒蕈碱受体相比，THA对高亲和力烟碱受体的亲和力低20倍。该研究表明，THA可能通过与毒蕈碱和烟碱异受体相互作用增强大鼠纹状体中的单胺神经传递。
