基于机制性药动药效学模型探讨脑α_2受体对脑5-HT的影响  

Exploring the effect of α_2 receptor on brain 5-HT via a mechanismbased pharmacodynamic model

作　　者：孙晶晶 胡路云[2,3] 林宝琴[3] 

机构地区：[1]广州医药研究总院有限公司药物非临床评价研究中心 [2]中国药科大学中药学院 [3]广州中医药大学中药学院

出　　处：《中国临床药理学与治疗学》2015年第6期660-664,693,共6页Chinese Journal of Clinical Pharmacology and Therapeutics

摘　　要：目的:以雄性Wistar大鼠脑中缝背核(dorsal raphe nuclei,DRN)和脑前额区(prefrontal cortex,PFC)作为研究脑区,在选择性5-羟色胺(5-serotonin,5-HT)重摄取抑制剂和去甲肾上腺素重摄取抑制剂合用情况下,给予不同浓度的α2受体拮抗剂BRL44408,建立机制性药动药效学模型,考察α2异型受体对DRN和PFC中5-HT浓度的影响。方法:采用微透析法给予DRN不同浓度的BRL44408,检测DRN和PFC中5-HT浓度,用Winnolin软件建立机制性药代药效模型,利用该模型进行参数估计及对模型进行外推模拟。结果:该模型成功拟合BRL44408在2个剂量水平下的DRN和PFC中5-HT的浓度数据。并在模型的基础上外推模拟BRL444083个剂量水平下的DRN和PFC中5-HT的浓度变化。直接观察和模型诊断结果显示,随着DRN中BRL44408剂量增加,DRN和PFC中5-HT的浓度也增加。结论:该模型较好地拟合DRN和PFC中5-HT浓度,为进一步开展脑内α2受体对脑内5-HT浓度的调节能力研究提供参考。AIM： A mechanism based on pharmacodynamic model was developed by using set of modified indirect models to observe the inhibition effect of α2adrenoceptors on serotonin level in dosal raphé nucleus（ DRN）,prefrontal cortex（ PFC） under serotonin and norepinephrine dual reuptake inhibition condition. METHODS： Using the microdialysis method, after infusion of an α2antagonist（ BRL44408） in DRN,the DRN and PFC serotonin time course data of male Wistar rats were collected under the combination of serotonin reuptake inhibition and norepinephrine reuptake inhibition in DRN.The serotonin level data from both DRN and PFC were simultaneously fitted using the model and Winnolincomputer program. RESULTS： The serotonin level in DRN and PFC increased with the dose of BRL44408 increased in DRN. The model estimation and simulation results suggested the varied modulation property of α2adrenoceptors located in DRN on regulating the DRN serotonin level and the PFC serotonin level under dual reuptake inhibition. CONCLUSION： The proposed model successfully captures the time course of serotonin in both DRN and PFC at two dose schemes of BRL44408 and provide meaningful estimation and simulation on regulation capability of α2heteroreceptors in DRN under dual reuptake inhibition.

关 键 词：5-羟色胺 BRL44408 机制性药效学模型 α2异型受体 

分 类 号：R969[医药卫生—药理学]