Batool Farhat, Haleem Muhammad A, Haleem Darakhshan J
Neurochemistry and Biochemical Neuropharmacology Research Laboratory, Dept of Biochemistry, University of Karachi, Karachi-75270, Pakistan.
Sci Pharm. 2010 Apr-Jun;78(2):259-74. doi: 10.3797/scipharm.0907-20. Epub 2009 Nov 29.
The present study compares the extrapyramidal and neurochemical effects of clozapine and risperidone in rat caudate (corpus striatum) and nucleus accumbens (ventral striatum) dose-dependently. Animals injected with clozapine (2.5, 5.0 and 10.0 mg/kg IP) or risperidone (1.0, 2.5 and 5.0 mg/kg IP) in acute were sacrificed 1 h later to collect brain samples. Extrapyramidal side effects (EPS) in terms of locomotor activity and catalepsy were monitored in each animal after the drug or vehicle administration. Maximum cataleptic potentials were found only at high doses of clozapine (10.0 mg/kg; 60%) and risperidone (5.0 mg/kg; 100%). Neurochemical estimations were carried out by HPLC-EC. Both drugs at all doses significantly (p<0.01) increased the concentration of homovanillic acid (HVA), a metabolite of DA, in the caudate nucleus and decreased in nucleus accumbens. Levels of Dihydroxyphenylacetic acid (DOPAC) significantly (p<0.01) increased in the caudate by clozapine administration and decreased in the nucleus accumbens by the administration of both drugs in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin significantly decreased in the caudate and nucleus accumbens in a similar fashion. Levels of tryptophan (TRP) were remained insignificant in caudate and nucleus accumbens by the injections of two drugs. In caudate, clozapine and risperidone administrations significantly (p<0.01) decreased HVA/DA ratio and increased DOPAC/DA ratio in nucleus accumbens at all doses. The findings suggest the evidence for DA/5-HT receptor interaction as an important link in the lower incidence of EPS. The possible role of serotonin(1A) receptors in the pathophysiology of schizophrenia is also discussed.
本研究剂量依赖性地比较了氯氮平和利培酮对大鼠尾状核（纹状体）和伏隔核（腹侧纹状体）的锥体外系和神经化学作用。急性注射氯氮平（2.5、5.0和10.0mg/kg腹腔注射）或利培酮（1.0、2.5和5.0mg/kg腹腔注射）的动物在1小时后处死以收集脑样本。给药后，监测每只动物在运动活性和僵住症方面的锥体外系副作用（EPS）。仅在高剂量氯氮平（10.0mg/kg；60%）和利培酮（5.0mg/kg；100%）时发现最大僵住症潜能。通过高效液相色谱-电化学检测法进行神经化学评估。所有剂量的两种药物均显著（p<0.01）增加了尾状核中多巴胺代谢产物高香草酸（HVA）的浓度，而伏隔核中的HVA浓度降低。氯氮平给药使尾状核中二羟基苯乙酸（DOPAC）水平显著（p<0.01）升高，两种药物给药均使伏隔核中的DOPAC水平呈剂量依赖性降低。5-羟色胺主要代谢产物5-羟吲哚乙酸（5-HIAA）在尾状核和伏隔核中以类似方式显著降低。两种药物注射后，尾状核和伏隔核中色氨酸（TRP）水平无显著变化。在尾状核中，所有剂量的氯氮平和利培酮给药均显著（p<0.01）降低HVA/多巴胺比值，增加伏隔核中DOPAC/多巴胺比值。这些发现表明多巴胺/5-羟色胺受体相互作用是EPS发生率较低的重要环节。还讨论了5-羟色胺（1A）受体在精神分裂症病理生理学中的可能作用。
