小鼠两瓶自由选择模型上加波沙朵的精神依赖作用OACSTPCD
Psychological dependence liability of gaboxadol in two-bottle free-choice model in mice
目的 利用小鼠两瓶自由选择模型评价突触外γ-氨基丁酸A型受体(GABAAR)激动剂加波沙朵的精神依赖性,并与突触内GABAAR变构调节剂咪达唑仑比较.方法 ①C57BL/6J雄性小鼠分别ig给予溶剂、咪达唑仑(59.0,73.7,92.2,115.2,144.0和180.0 mg·kg-1)或加波沙朵(8.4,10.5,13.1,16.4,20.5,25.6和32.0 mg·kg-1)后进行翻正反射行为观察,通过翻正反射消失量效曲线计算两药的半数有效量(ED50).②在两瓶自由选择模型上评价加波沙朵或咪达唑仑是否诱导小鼠产生偏好行为.小鼠分为正常对照、加波沙朵或咪达唑仑组.在两瓶自由选择实验的适应期(第1～3天)测试瓶和溶剂对照瓶均装入饮用水,训练期(第4～5天)两瓶均更换为4%蔗糖溶液,测试期(第6～15天)测试瓶分别装入含溶剂、加波沙朵(3.9×10-6 mol·L-1)或咪达唑仑(1.4×10-5 mol·L-1)的蔗糖溶液,溶剂对照瓶分别装入含相应溶剂的蔗糖溶液,置于饲养笼两侧.小鼠自由选择两瓶饮用,分别记录测试瓶和溶剂对照瓶每日饮用量,计算每日总饮用量、测试期内药液累计饮用量、相对饮用量和测试期内累计相对饮用量,并每日记录小鼠体重.结果 ①咪达唑仑和加波沙朵均剂量依赖性地增加小鼠翻正反射消失率,ED50分别为咪达唑仑105.3 mg·kg-1(95%Cl:96.4～115.2 mg·kg-1,R2=0.9796)、加波沙朵13.7 mg·kg-1(95%Cl:12.6～15.0 mg·kg-1,R2=0.9773).②与正常对照组相比,加波沙朵组和咪达唑仑组每日总饮用量无显著变化;咪达唑仑组在测试期第11～15天测试瓶每日饮用量较同组溶剂对照瓶显著增加(P<0.05),测试期内加波沙朵组测试瓶每日饮用量也显著升高(P<0.01).与正常对照组比较,咪达唑仑组和加波沙朵组测试瓶累计饮用量无统计学差异;加波沙朵组第9天的每日相对饮用量显著增加(P<0.05),测试期累计相对饮用量也显著增高(P<0.01).各组小鼠体重变化无显著性差异.结论 在两瓶自由选择模型上,咪达唑仑和加波沙朵均诱导小鼠产生饮用偏好,提示加波沙朵可能也存在精神依赖潜能.
OBJECTIVE To evaluate the psychological dependence of the extrasynaptic GABAA receptor(GABAAR)agonist gaboxadol and compare it with the synaptic GABAAR modulator midazolam in the two-bottle free-choice model of mice.METHODS ① Male C57BL/6J mice were ig administered with vehicle,midazolam(59.0,73.7,92.2,115.2,144.0 and 180.0 mg·kg-1)or gaboxadol(8.4,10.5,13.1,16.4,20.5,25.6 and 32.0 mg·kg-1),and the loss of righting reflex was observed.The median effective dose(ED50)was obtained from the dose-response curve.② A two-bottle free-choice model was used to find out whether gaboxadol and midazolam induced preference behavior in mice.The mice were divided into normal control,gaboxadol or midazolam groups.During the habituation stage(the first day to the third day,D1-D3),both test and vehicle bottles contained water.During the trail stage(D4-D5),4%sucrose solution was provided in both bottles.During the test stage(D6-D15),test bottles contained vehicle,gaboxadol(3.9×10-6 mol·L-1)or midazolam(1.4×10-5 mol·L-1)in sucrose solu-tions,while other bottles contained the corresponding vehicle in sucrose solutions.Bottles were placed on the two sides of the home cage,to which mice had free access,and their consumption from each bottle was recorded daily.Total consumption,accumulated daily consumption,relative consumption,and accumulated relative consumption during the test stage were calculated.The weight of the mice was also recorded.RESULTS ① Midazolam and gaboxadol dose-dependently increased the rate of loss of right reflex in mice,with ED50 of 105.3 mg·kg-1(95%CI:96.4-115.2 mg·kg-1,R2=0.9796),13.7 mg·kg-1(95%CI:12.6-15.0 mg·kg-1,R2=0.9773),respectively.② Compared with the normal control group,there was no significant difference in the total consumption in the gaboxadol and midazolam groups.Compared to the vehicle bottles,the daily consumption from test bottles in the midazolam group increased significantly on D11-D15 of the test stage(P<0.05),while daily consumption from gaboxadol test bottles was significantly higher than that of vehicle bottles(P<0.01).Compared with the normal control group,the daily relative consumption in the gaboxadol group was significantly increased on D9(P<0.05),and the accumulative relative consumption was significantly higher than in the normal control group(P<0.01).There was no significant change in body weight across the groups over the test stage.CONCLU-SION Like midazolam,gaboxadol exhibits psychological dependence potential in a two-bottle free-choice model.
阿来·木合亚提;赵玉;俞纲;苏瑞斌
军事科学院军事医学研究院毒物药物研究所,抗毒药物与毒理学国家重点实验室,神经精神药理学北京市重点实验室,北京 100850
药学
咪达唑仑加波沙朵两瓶自由选择模型翻正反射消失精神依赖
midazolamgaboxadoltwo-bottle free-choice modelloss of righting reflexpsycholog-ical dependence
《中国药理学与毒理学杂志》 2024 (002)
97-104 / 8
评论