[Assessment of anxiolytics (6)--A novel method in mice using psychological stress]

Both antinociception induced by psychological stress (PSY, using the communication box) and the suppression by the stress of the development of antinociceptive tolerance to morphine were completely extinguished by diazepam (DZP, 1-2 mg/kg), suggesting an essential role of emotional factors in the underlying mechanisms. Based on these findings, a simple and selective method for evaluating anxiolytics was designed. Treatment with methysergide (2-20 mg/kg, ip), buspirone (1-10 mg/kg, ip), ritanserin (1-5 mg/kg, ip), Y-25,130 (0.03-0.1 mg/kg, ip) and ICS 205-930 (1-100 micrograms/kg, po), all of which reportedly possess anxiolytic activity, dose-dependently suppressed both the production of PSY stress-induced antinociception (PSY-SIA) and the blockade of the development of morphine tolerance by PSY stress. In contrast to these compounds, (+/-)pindolol (up to 3 mg/kg) and imipramine, even after pretreatment daily with 40 mg/kg, ip, for 5 days, produced no such suppression. In an elevated plus-maze (EPM) method, frequently used as a simple method for detecting anxiolytic drugs, not only DZP, buspirone, Y-25,130 and ICS 205-930 but also imipramine (daily with 40 mg/kg for 5 days) increased the time spent on the open arms, while methysergide or retanserin failed to augment the time, indicating that the EPM method is not selective for this purpose. Since U-50,488H suppresses the development of morphine tolerance, the utility of the compound for PSY stress was also examined; however, the suppressive effect was counteracted by (+/-)pindolol but not by ritanserin. Thus, we proposed a valid new method for screening anxiolytic drugs in mice, by testing the extinguishable effect of drugs on these parameters, i.e., PSY-SIA and suppression by PSY stress of the development of morphine tolerance.