Molecular biological study of mechanism of action of atypical antipsychotic drugs

用氟哌啶醇(HPD)0.1 mg/kg、HPD/氟伏沙明(Flv)25 mg/kg和利培酮(RIS)0.5 mg/kg/flv处理大鼠3周，观察其对纹状体D_2受体结合的影响。与对照组相比，HPD/FLV亚慢性处理可显著增强HPD诱导的D2受体表达上调，而RIS/FLV亚慢性处理未见明显增加。这些结果表明，阻断5-羟色胺受体可阻止SSRI和HPD共同作用引起的D_2受体上调，锥体外系症状和迟发性运动障碍的发生率可能较低，不仅在RIS单独治疗的情况下，而且在RIS和SSRI联合治疗的情况下也是如此。用径向迷宫实验观察了长期使用锂对大鼠工作记忆和参照记忆的影响。在口服锂的开始和一周后，工作记忆和参照记忆都比对照组有显著改善。两组在体重、运动能力和食欲方面没有显著差异。D_1受体激动剂SKF82958诱导的运动活动在锂处理组大鼠较对照组显著增强。Western blotting检测结果显示，给锂后第14天和第28天，额叶皮质D_1受体蛋白表达显著增加，而精核和纹状体则无明显变化。额叶皮质D1受体基因表达在第6、14、28天显著增加，伏隔核和纹状体在28天明显减少。长期服用锂可能通过促进额叶皮质D_1受体基因转录，从而改善认知功能。

The effects of 3-week treatment with haloperidol (HPD 0.1 mg/kg), HPD/fluvoxamine (FLV 25 mg/kg) and risperidone (RIS 0.5mg/kg)/FLV on the binding to D_2 receptors were examined in the rat striatum. Subchronic treatment with HPD/FLV significantly enhanced D_2 receptor up-regulation induced by HPD alone, while no increase was observed with RIS/FLV compared to controls. These findings suggest that 5-HT_<2A> receptor blockade prevents the enhanced D_2 receptor up-regulation induced by coadministration of SSRI with HPD and that the frequency of extrapyramidal symptoms and tardive dyskinesia may be low not only in case of treatment with RIS alone, but also in case of cotreatment with RIS and SSRI.The effect of long-term treatment with lithium on working memory and referrence memory was examined in the rat using radial maze test. Both working and referrence memory were significantly improved compared to controls on the beginning and one week after oral administration of lithium, respectively. No significant differences were found between the two groups in body weight, locomotor activity and appetite. The D_1 receptor agonist SKF82958-induced locomotor activity was significantly enhanced in the lithium-treated rat compared with controls. The D_1 receptor protein measured by Western blotting was significantly increased in the frontal cortex on 14 days and 28 days after lithium administration, but no changes were observed in the nucleus accurnbens and striatum. The D1 receptor mRNA in frontal cortex was increased on 6, 14 and 28 days, while it was significantly decreased in the nucleus accumbens and striatum on 28 days. It is possible that long-term treatment with lithium may improve cognitive function by the mechanism of enhanced transcription of the D_1 receptor gene in frontal cortex.