Roman S, Badia A, Camps P, Muñoz-Torrero D, Clos M V
Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Institut de Neurociències Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
Brain Res. 2005 Nov 9;1061(2):73-9. doi: 10.1016/j.brainres.2005.07.042. Epub 2005 Oct 24.
The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors.
本研究的主要目的是分析对烟碱样受体具有增强作用的（±）-石杉碱甲（（±）-HX）和加兰他敏（GAL）以及缺乏烟碱样活性的石杉碱A（HPA）对大鼠脑纹状体切片中[3H]-乙酰胆碱（[3H]-ACh）释放的影响。所有化合物均为乙酰胆碱酯酶的非共价可逆抑制剂。向灌流培养基中添加（±）-HX（0.01微摩尔）、GAL（10微摩尔）和HPA（0.1微摩尔）可使乙酰胆碱神经递质的释放减少到相似程度：分别为36%、30%和34%（P<0.01）。在阻断突触前毒蕈碱M₂受体的阿托品（ATR；0.1微摩尔）存在的情况下，这种作用得以逆转。此后，在多巴胺D₂拮抗剂氟哌啶醇（HAL；0.01微摩尔）存在的情况下，研究了一系列浓度的药物与ATR（0.1微摩尔）同时存在时的情况。在这些条件下，在（±）-HX、GAL和HPA存在时观察到[3H]-ACh释放呈剂量依赖性增加。为了测试烟碱样受体在药物对[3H]-ACh释放的作用中的作用，使用100微摩尔的美加明（MEC）来阻断此类受体。单独使用MEC可使神经递质释放显著减少18%（P<0.05），但在ATR和MEC同时存在时未观察到变化。在这些条件下，（±）-HX、GAL和HPA分别使[3H]-ACh的释放增加了37%、25%和38%（P<0.01）。考虑到所有这些数据，目前的结果表明，（±）-HX和GAL这两种烟碱样受体增强剂所诱导的作用似乎主要归因于它们抑制乙酰胆碱酯酶活性的能力，而非通过与烟碱样受体相互作用。
