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.