5-羟色胺3受体拮抗剂对大鼠中脑边缘多巴胺能通路选择性激活反应的影响。
Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat.
作者信息
Hagan R M, Jones B J, Jordan C C, Tyers M B
机构信息
Department of Neuropharmacology, Glaxo Group Research Ltd., Ware, Hertfordshire.
出版信息
Br J Pharmacol. 1990 Feb;99(2):227-32. doi: 10.1111/j.1476-5381.1990.tb14685.x.
Abstract
- The effects of 5-hydroxytryptamine3 (5-HT3) receptor antagonists on the behavioural hyperactivity response which results from injection of the neurokinin receptor agonist [pGlu5, MePhe8, Sar9]-substance P (5-11) (DiMe-C7) into the ventral tegmental area (VTA) of the rat midbrain have been determined. 2. Subcutaneous administration of ondansetron (GR38032) (0.001-0.3 mg kg-1), GR65630 (0.01 mg kg-1), ICS 205-930 (0.1 mg kg-1) and MDL 72222 (0.1 mg kg-1), inhibited the DiMe-C7-induced hyperactivity response. 3. The effects of ondansetron on DiMe-C7-induced changes in dopamine and 5-HT metabolism in discrete areas of rat forebrain were studied in order to investigate further the possible mechanism of action of 5-HT3 antagonists in modifying mesolimbic dopaminergic systems. 4. Intra-VTA administration of DiMe-C7 increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens, olfactory tubercules and right amygdala, indicating increased mesolimbic dopamine metabolism. DOPAC levels were not significantly increased in the frontal cortex, left amygdala or striatum. Dopamine levels were not altered in any of these brain areas. DiMe-C7 also increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the amygdala but this was only statistically significant in the right amygdala. 5-HT levels were not changed significantly by DiMe-C7 treatment. 5. In control rats, pretreatment with ondansetron (0.1 mg kg-1) had no effect on the levels of dopamine, 5-HT or their metabolites, but in rats given DiMe-C7, ondansetron significantly inhibited the increase in DOPAC levels in the nucleus accumbens. 6. These results are in agreement with the proposed facilitatory role of 5-HT3 receptor activation on mesolimbic dopaminergic transmission, and suggest that 5-HT3 antagonists may have important therapeutic indications for the treatment of CNS disorders in which mesolimbic dopamine systems are perturbed.
摘要
- 已确定5-羟色胺3（5-HT3）受体拮抗剂对将神经激肽受体激动剂[焦谷氨酸5、苯丙氨酸8、肌氨酸9]-P物质（5-11）（二甲基-C7）注射到大鼠中脑腹侧被盖区（VTA）所引起的行为多动反应的影响。2. 皮下注射昂丹司琼（GR38032）（0.001 - 0.3毫克/千克）、GR65630（0.01毫克/千克）、ICS 205 - 930（0.1毫克/千克）和MDL 72222（0.1毫克/千克）可抑制二甲基-C7诱导的多动反应。3. 研究了昂丹司琼对二甲基-C7诱导的大鼠前脑离散区域多巴胺和5-羟色胺代谢变化的影响，以进一步研究5-HT3拮抗剂调节中脑边缘多巴胺能系统的可能作用机制。4. 向VTA内注射二甲基-C7可使伏隔核、嗅结节和右侧杏仁核中的二羟基苯乙酸（DOPAC）水平升高，表明中脑边缘多巴胺代谢增加。额叶皮质、左侧杏仁核或纹状体中的DOPAC水平未显著升高。这些脑区中的多巴胺水平未发生改变。二甲基-C7还可使杏仁核中的5-羟吲哚乙酸（5-HIAA）水平升高，但仅在右侧杏仁核中具有统计学意义。二甲基-C7处理后5-羟色胺水平未显著改变。5. 在对照大鼠中，用昂丹司琼（0.1毫克/千克）预处理对多巴胺、5-羟色胺或其代谢产物水平无影响，但在给予二甲基-C7的大鼠中，昂丹司琼可显著抑制伏隔核中DOPAC水平的升高。6. 这些结果与5-HT3受体激活对中脑边缘多巴胺能传递的促进作用一致，并表明5-HT3拮抗剂可能对治疗中脑边缘多巴胺系统受到干扰的中枢神经系统疾病具有重要的治疗指征。
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