Nowak P, Szczerbak G, Biedka I, Drosik M, Kostrzewa R M, Brus R
Department of Pharmacology, Medical University of Silesia, Zabrze, Poland.
J Physiol Pharmacol. 2006 Dec;57(4):583-97.
5-HT(2A/2C) receptors are one of the most important in controlling basal ganglia outputs. In rodent models of Parkinson's disease (PD) blockade of these receptors increases locomotion and enhances the actions of dopamine (DA) replacement therapy. Moreover, previously we established that 5-HT(2A/2C) antagonist attenuate DA D(1) agonist mediated vacuous chewing movements (VCMs) which are considered as an animal representation of human dyskinesia. These findings implicate 5-HT neuronal phenotypes in basal ganglia pathology, and promote 5-HT(2) antagonists as a rational treatment approach for dyskinesia that is prominent in most instances of PD replacement therapy. In the current study we determined whether ketanserin (KET) and/or amphetamine (AMPH) affected dopaminergic neurotranssmision in intact and fully DA-denervated rats. Moreover, we looked into extraneuronal content of HO. of the neostriatum after AMPH and/or KET injection, assessed by HPLC analysis of dihydroxybenzoic acids (2,3- and 2, 5-DHBA) - spin trap products of salicylate. Findings from the present study demonstrated that there are no substantial differences in extraneuronal HO. generation in the neostriatum between control and parkinsonian rats. KET did not affect DA release in the fully DA-denervated rat's neostriatum and also did not enhance HO. production. As 5-HT(2A/2C) receptor-mediated transmission might prove usefulness not only in addressing motor complications of PD patients (dyskinesia) but also in addressing non-motor problems such depression and/or L-DOPA evoked psychosis, the findings from the current study showed that the use of 5-HT(2A/2C) receptor antagonists in Parkinson's disease does not impend the neostriatal neuropil to be damaged by these drugs. We concluded that 5-HT(2A/2C) receptor antagonists may provide an attractive non-dopaminergic target for improving therapies for some basal ganglia disorders.
5-羟色胺（5-HT，2A/2C）受体是控制基底神经节输出的最重要受体之一。在帕金森病（PD）的啮齿动物模型中，阻断这些受体可增加运动能力，并增强多巴胺（DA）替代疗法的效果。此外，我们之前证实5-HT（2A/2C）拮抗剂可减轻DA D（1）激动剂介导的空嚼运动（VCMs），而VCMs被认为是人类运动障碍的动物模型。这些发现表明5-HT神经元表型与基底神经节病理有关，并促使5-HT（2）拮抗剂成为治疗运动障碍的合理方法，运动障碍在大多数PD替代疗法中都很突出。在本研究中，我们确定了酮色林（KET）和/或苯丙胺（AMPH）是否会影响完整和完全去多巴胺能大鼠的多巴胺能神经传递。此外，我们研究了注射AMPH和/或KET后新纹状体中羟基自由基（HO.）的细胞外含量，通过对二羟基苯甲酸（2,3-和2,5-DHBA）——水杨酸的自旋捕获产物进行高效液相色谱分析来评估。本研究结果表明，对照大鼠和帕金森病大鼠新纹状体中的细胞外HO.生成没有实质性差异。KET不影响完全去多巴胺能大鼠新纹状体中的DA释放，也不增强HO.的产生。由于5-HT（2A/2C）受体介导的传递可能不仅对解决PD患者的运动并发症（运动障碍）有用，而且对解决非运动问题如抑郁和/或左旋多巴诱发的精神病也有用，本研究结果表明，在帕金森病中使用5-HT（2A/2C）受体拮抗剂不会使新纹状体神经纤维受到这些药物的损害。我们得出结论，5-HT（2A/2C）受体拮抗剂可能为改善某些基底神经节疾病的治疗提供一个有吸引力的非多巴胺能靶点。
