Molecular biological study of mechanism of action of atypical antipsychotic drugs

非典型抗精神病药物作用机制的分子生物学研究

• 批准号: 13670978
• 负责人: KUSUMI Ichiro
• 金额: $ 2.3万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670978/
• 关键词: Atypical antipsychotic drug; Serotonin-2A receptor; Dopamine-2 receptor; SSRI; Lithium; Working memory; Dopamine-1 receptor; Frontal cortex; セロトニン5-HT2A受容体; 定型抗精神病薬; 錐体外路症状; 遅発性ジスキネジア; citalopram; methamphetamine; ドパミンD_2受容体; D_2 mRNA; 遺伝子

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.

本文观察了氟哌啶醇（HPD 0.1mg/kg）、HPD/氟伏沙明（FLV 25 mg/kg）和利培酮（RIS 0.5mg/kg）/FLV治疗3周后对大鼠纹状体D_2受体结合的影响。与对照组相比，HPD/FLV亚慢性处理显著增强了HPD单独诱导的D_2受体上调，而RIS/FLV亚慢性处理没有观察到增加。这些结果提示，5-HT_2<2A>受体阻断剂可抑制SSRI和HPD联合应用所引起的D_2受体上调，并提示RIS单独治疗以及RIS和SSRI联合治疗均可降低锥体外系症状和迟发性运动障碍的发生率。与对照组相比，口服锂开始时和口服锂后一周，工作记忆和重复记忆均显著改善。两组间体重、自主活动和食欲无显著差异。与对照组相比，D_1受体激动剂SKF 82958在锂处理的大鼠中诱导的自发活动显著增强。用Western blotting法检测到，注射锂后14 d和28 d，额叶皮质D_1受体蛋白明显增加，而伏隔核和纹状体D_1受体蛋白无明显变化。额叶皮质D1受体mRNA在6、14和28 d时表达增加，而纹状体和中脑核D1受体mRNA在28 d时表达明显减少。长期锂治疗可能通过增强额叶D_1受体基因转录而改善认知功能。

项目成果

久住一郎 他: "従来型あるいは非定型抗精神病薬からquetiapineへの切り替え症例の検討"臨床精神薬理. 5(増刊). 335-342 (2002)

Ichiro Kusumi 等人：“从传统或非典型抗精神病药转为喹硫平的病例研究”临床精神药理学 5（特别版）335-342（2002 年）。

高橋義人 他: "治療抵抗性分裂病"Schizophrenia Practice. 6. 1-13 (2002)

Yoshito Takahashi 等人：“难治性精神分裂症”精神分裂症实践。 6. 1-13 (2002)

Kameda K.: "Effects of lithium on dopamine D2 receptor expression in the rat striatum"J Neural Transm. 108. 321-334 (2001)

Kameda K.：“锂对大鼠纹状体多巴胺 D2 受体表达的影响”J Neural Transm。

久住一郎他: "従来型あるいは非定型抗精神病薬からquetiapineへの切り替え症例の検討"臨床精神薬理. 5(増刊). 335-342 (2002)

Ichiro Kusumi 等人：“从传统或非典型抗精神病药转为喹硫平的病例研究”临床精神药理学 5（特别版）335-342（2002 年）。

Kusumi I: "Exchange from conventional and atypical antipsychotic drugs into quetiapine for schizophrenic patients (in Japanese)"Jpn J Clin Psychopharmacology. 5 (suppl). 335-342 (2002)

Kusumi I：“精神分裂症患者从传统和非典型抗精神病药物换成喹硫平（日语）”Jpn J Clin Psychopharmacology。