Rodgers R J, Evans P M, Murphy A
Behavioural Neuroscience Laboratory, Institute of Psychological Sciences, University of Leeds, England, UK.
Behav Pharmacol. 2005 Sep;16(5-6):405-13. doi: 10.1097/00008877-200509000-00013.
The notoriously inconsistent effects of cannabinoids on anxiety-like behaviour may be explained by recent research on CB1 receptor knockout (CB1-KO) mice suggesting that cannabinoids exert bidirectional effects via the CB1 receptor (anxiolysis) and a novel rimonabant-sensitive neuronal cannabinoid receptor (anxiogenesis). This hypothesis is supported by the anxiogenic-like profile of AM-251, an analogue of rimonabant that is a potent and selective CB1 receptor antagonist but which, unlike rimonabant, has no activity at the novel receptor. As we have previously shown that rimonabant reduces anxiety-like behaviour in test-experienced animals only, the current study assessed the effects of AM-251 (1.5-3.0 mg/kg) in male Swiss-Webster mice that were either plus-maze-naïve or had been exposed undrugged to the apparatus 24 h prior to testing. Results confirmed that prior maze experience per se significantly increases behavioural indices of anxiety without altering measures of general activity. In maze-naïve mice, the lower dose of AM-251 (1.5 mg/kg) significantly reduced % open-arm time and increased grooming while the higher dose (3.0 mg/kg) additionally reduced open-arm entries and total head-dipping, and increased closed-arm returns. These anxiogenic-like effects were observed in the absence of significant changes in general activity levels. Although AM-251 had a very similar profile in maze-experienced animals, significant drug effects on open-arm avoidance measures were precluded by experientially-induced changes in behavioural baselines (i.e. 'ceiling' effects). Nevertheless, AM-251 again significantly reduced total head-dipping and increased grooming (3.0 mg/kg) and, unlike effects in naïve animals, both doses markedly reduced time spent on the centre platform and increased time spent in the enclosed arms. Against a baseline of almost total open-arm avoidance, the pattern of behavioural change in maze-experienced mice would also be consistent with an anxiogenic-like action of AM-251. Data are discussed in relation to previous findings with rimonabant, the putative existence of a novel non-CB1 neuronal cannabinoid receptor and, more generally, the behavioural pharmacology of plus-maze 'trial 2'.
大麻素对焦虑样行为的影响向来不一致，近期对CB1受体基因敲除（CB1-KO）小鼠的研究或许可以解释这一现象。该研究表明，大麻素通过CB1受体发挥双向作用（抗焦虑），并通过一种新型的对利莫那班敏感的神经元大麻素受体发挥作用（致焦虑）。这一假说得到了AM-251致焦虑样特征的支持。AM-251是利莫那班的类似物，是一种强效且选择性的CB1受体拮抗剂，但与利莫那班不同的是，它对新型受体无活性。正如我们之前所表明的，利莫那班仅在有测试经验的动物中能减少焦虑样行为，因此本研究评估了AM-251（1.5 - 3.0毫克/千克）对雄性瑞士韦伯斯特小鼠的影响，这些小鼠要么从未接触过十字迷宫，要么在测试前24小时未用药的情况下接触过该装置。结果证实，先前的迷宫经验本身会显著增加焦虑的行为指标，而不会改变一般活动的测量值。在从未接触过迷宫的小鼠中，较低剂量的AM-251（1.5毫克/千克）显著减少了在开放臂的停留时间百分比，并增加了理毛行为，而较高剂量（3.0毫克/千克）则进一步减少了进入开放臂的次数和总的探头次数，并增加了返回封闭臂的次数。在一般活动水平没有显著变化的情况下观察到了这些致焦虑样效应。尽管AM-251在有迷宫经验的动物中具有非常相似的特征，但行为基线的经验性诱导变化（即“天花板”效应）排除了药物对开放臂回避测量的显著影响。然而，AM-251再次显著减少了总的探头次数，并增加了理毛行为（3.0毫克/千克），与对未接触过迷宫的动物的影响不同，这两个剂量都显著减少了在中央平台停留的时间，并增加了在封闭臂停留的时间。在几乎完全回避开放臂的基线情况下，有迷宫经验的小鼠的行为变化模式也与AM-251的致焦虑样作用一致。我们将结合先前利莫那班的研究结果、假定存在的新型非CB1神经元大麻素受体，以及更广泛地说，十字迷宫“第二次试验”的行为药理学来讨论这些数据。
