Jackisch R, Link T, Neufang B, Koch R
Department of Pharmacology, University of Freiburg, Germany.
Arch Int Pharmacodyn Ther. 1992 Nov-Dec;320:21-42.
The effects of the antiparkinsonian drugs amantadine and memantine and of the noncompetitive NMDA receptor antagonist MK-801 were studied in the model of the electrically evoked release of [3H]dopamine and [3H]acetylcholine in slices of the rabbit caudate nucleus in vitro. In the [3H]dopamine release model, high concentrations (> 10 microM) of the drugs investigated showed a marked increase in spontaneous 3H-efflux, with the following order of potency: memantine > MK-801 > amantadine. The spontaneous 3H-efflux induced by 50 microM memantine was diminished by pargyline (10 microM), but was insensitive to the presence of tetrodotoxin (0.3 microM), or nomifensine (1 microM), or to the omission of Ca2+ in the superfusion medium; in the absence of nomifensine it consisted mainly of 3H-metabolites of dopamine. The latter findings indicate that the memantine-induced spontaneous 3H-efflux is unrelated to the firing of striatal interneurons but point to a direct releasing effect of memantine on dopaminergic storage granules. On the other hand, the electrically evoked release of [3H]dopamine seemed to be unaffected by memantine, was only slightly reduced by amantadine but significantly inhibited by MK-801. In the model of the electrically evoked release of [3H]acetylcholine, only MK-801 (> 50 microM) showed significant inhibitory effects, both on spontaneous and evoked overflow of [3H]acetylcholine; the effects of memantine and amantadine were negligible. Since only high concentrations of amantadine and memantine (exceeding those which, according to the literature, may be reached in vivo) showed effects in the present in vitro dopamine and acetylcholine release models, it is concluded that the clinical efficacy of these antiparkinsonian drugs is most probably unrelated to an enhancement of dopaminergic transmission as suggested from earlier in vitro and in vivo findings. The higher activity of MK-801 in the present model and the recent observation that both memantine and amantadine bind--although with lower affinity--to an MK-801 binding site in the NMDA receptor-linked ion channel, suggest a possible involvement of striatal NMDA receptors in the antiparkinsonian effects of these drugs.
在体外兔尾状核切片中电诱发[3H]多巴胺和[3H]乙酰胆碱释放的模型中，研究了抗帕金森病药物金刚烷胺和美金刚以及非竞争性NMDA受体拮抗剂MK-801的作用。在[3H]多巴胺释放模型中，所研究药物的高浓度（>10μM）显示出自发性3H外流显著增加，效力顺序如下：美金刚>MK-801>金刚烷胺。50μM美金刚诱导的自发性3H外流被帕吉林（10μM）减弱，但对河豚毒素（0.3μM）、诺米芬辛（1μM）的存在不敏感，对灌流培养基中Ca2+的缺失也不敏感；在没有诺米芬辛的情况下，它主要由多巴胺的3H代谢产物组成。后一发现表明，美金刚诱导的自发性3H外流与纹状体中间神经元的放电无关，但表明美金刚对多巴胺能储存颗粒有直接释放作用。另一方面，[3H]多巴胺的电诱发释放似乎不受美金刚影响，仅被金刚烷胺轻微降低，但被MK-801显著抑制。在[3H]乙酰胆碱电诱发释放模型中，只有MK-801（>50μM）对[3H]乙酰胆碱的自发性和诱发性溢出均显示出显著抑制作用；美金刚和金刚烷胺的作用可忽略不计。由于只有高浓度的金刚烷胺和美金刚（超过根据文献在体内可能达到的浓度）在目前的体外多巴胺和乙酰胆碱释放模型中显示出作用，因此得出结论，这些抗帕金森病药物的临床疗效很可能与早期体外和体内研究结果所表明的多巴胺能传递增强无关。MK-801在目前模型中的较高活性以及最近观察到美金刚和金刚烷胺虽然亲和力较低，但都与NMDA受体相关离子通道中的MK-801结合位点结合，提示纹状体NMDA受体可能参与了这些药物的抗帕金森病作用。
