University of Sunderland, Sunderland Pharmacy School, Sunderland, UK. abdel
Behav Brain Res. 2010 May 1;209(1):154-64. doi: 10.1016/j.bbr.2010.01.039. Epub 2010 Feb 1.
Balb/c mice were exposed to an elevated platform that is extended on two opposite sides with lowered steep slopes. They were tested for 12min per session in 6 successive days. They received i.p. administration of either saline or one dose of diazepam (DZP 0.5, 1, 3mg/kg) in sessions 1-3, and saline in sessions 4 and 5. All groups of mice received a single dose of DZP (1mg/kg) in session 6. DZP produced inverted U-shaped dose-responses on the number of entries into different areas of the apparatus, with a peak in mean response at 1mg/kg whereas its effect on the duration of entries was mostly comparable between the 3 doses. It increased the number of crossings on the surface of the platform and facilitated entries onto the slopes. DZP-treated mice crossed frequently onto and spent longer time on the slopes in sessions 1-3 whereas saline-treated mice remained on the platform in sessions 1-6. Withdrawal of DZP in sessions 4-5 increased the latency of first entry and decreased the number and duration of entries onto the slopes which was reversed with the administration of 1mg/kg of DZP in the next session. This ON-OFF the drug may be due to the half-life of DZP which is very short in mice and rats ( approximately 0.88h). It also indicates that DZP-treated mice did not benefit from previous experience of entries onto the slopes which suggests a possible "state-dependent" effect. Administration of DZP after repeated exposures to the test did not facilitate entries onto the slopes but instead increased significantly the number of crossings on the surface of the platform; this increase was much higher than that observed in mice initially treated with DZP and exposed to the test. There is no evidence of habituation in saline-treated mice: the number of crossings on the platform was comparable between the first 5 sessions of the test. These results demonstrate that repeated exposures to the same anxiogenic environment resulted in avoidance responses developing tolerance and approach responses developing sensitization. They suggest that tolerance and sensitization are two opposite sides of the habituation process to the same stimulus and may account for the maintained state of anxiety.
Balb/c 小鼠被暴露在一个升高的平台上，该平台的两个相对侧延伸出倾斜的陡坡。它们在连续 6 天的 6 次测试中，每次测试 12 分钟。在第 1-3 次测试中，它们接受腹腔注射生理盐水或单次剂量的地西泮（DZP0.5、1、3mg/kg），而在第 4 和 5 次测试中接受生理盐水。所有小鼠组在第 6 次测试中接受单次剂量的 DZP（1mg/kg）。DZP 对进入仪器不同区域的次数呈倒 U 形剂量反应，在 1mg/kg 时出现平均反应峰值，而其对进入时间的影响在 3 个剂量之间基本相当。它增加了在平台表面的穿越次数，并促进了进入斜坡。在第 1-3 次测试中，接受 DZP 治疗的小鼠频繁地进入并在斜坡上花费更长时间，而接受生理盐水治疗的小鼠则在第 1-6 次测试中留在平台上。在第 4-5 次测试中停用 DZP 会增加首次进入的潜伏期，并减少进入斜坡的次数和时间，而在下一次测试中给予 1mg/kg 的 DZP 则会逆转这种情况。这种药物的 ON-OFF 可能是由于 DZP 的半衰期非常短，在小鼠和大鼠中约为 0.88 小时。这也表明，接受 DZP 治疗的小鼠没有从以前进入斜坡的经验中受益，这表明可能存在“状态依赖性”效应。在反复暴露于测试后给予 DZP 不会促进进入斜坡，但会显著增加平台表面的穿越次数；这一增加比最初接受 DZP 并接受测试的小鼠高得多。在接受生理盐水治疗的小鼠中没有观察到习惯化：在测试的前 5 次中，平台上的穿越次数相当。这些结果表明，反复暴露于相同的焦虑环境会导致回避反应产生耐受性，而接近反应产生敏感性。它们表明，耐受性和敏感性是对同一刺激的习惯化过程的两个相反方面，可能解释了焦虑的维持状态。
