Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice.
Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice.
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DOI：
10.1002/aur.1395
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发表时间：
2014-10
期刊：
影响因子：
4.7
通讯作者：
Ragozzino, Michael E.
中科院分区：
文献类型：
--
作者：
Amodeo, Dionisio A.;Jones, Joshua H.;Sweeney, John A.;Ragozzino, Michael E.
自闭症中的受限兴趣和重复行为可能导致在日常活动和决策中“坚持同一性”。当外部情况发生变化时改变选择模式的能力通常被称为认知灵活性。到目前为止，治疗自闭症认知不灵活的方法有限。利培酮是一种非典型抗精神病药物，被批准用于治疗自闭症的易激惹症状，但对于它是否能有效治疗认知不灵活则知之甚少。利培酮作用于多种受体，尽管只有其中一部分受体的作用可能对认知灵活性有益。5 - HT2A受体阻断是利培酮的一种药理作用。啮齿动物研究表明，5 - HT2A受体拮抗剂可提高注意力和认知灵活性。本研究调查了利培酮和/或M100907（一种5 - HT2A受体拮抗剂）是否能改善BTBR自闭症小鼠模型的认知灵活性。与C57BL/6J（B6）小鼠相比，BTBR小鼠在逆转已习得的选择模式方面存在缺陷，这与自闭症患者的情况类似。本实验采用了一种二选一概率逆转学习测试，在该测试中，“正确”选择在80%的试验中得到强化，“错误”选择在20%的试验中得到强化。在初始习得之后，条件发生逆转。利培酮和M100907都改善了BTBR小鼠的概率逆转学习表现。相同的处理并没有改善B6小鼠的逆转学习。因为利培酮常常会导致不良副作用，所以使用5 - HT2A受体拮抗剂进行治疗可能为改善自闭症患者的认知灵活性提供一种替代方法。
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交互动受损以及存在受限兴趣和重复行为（RRBs）。RRBs会严重限制日常生活，并且会给家庭成员带来特别大的压力。到目前为止，治疗ASD这一特征的方法有限。利培酮是一种非典型抗精神病药物，被批准用于治疗ASD的易激惹症状，但对于它是否能有效治疗“高阶”RRBs，例如认知不灵活，则了解较少。利培酮也有多个受体靶点，其中只有一部分可能促进认知，而其他的则会导致认知障碍。5 - HT2A受体阻断是一种有前景且更具针对性的方法，因为各种临床前研究表明，5 - HT2A受体拮抗剂可改善认知。本研究调查了利培酮和/或M100907（一种5 - HT2A受体拮抗剂）是否能改善BTBR T + tf/J（BTBR）自闭症小鼠模型的概率逆转学习表现。还在C57BL/6J（B6）小鼠中作为对照品系研究了这些处理的效果。采用具有80/20概率反馈的空间逆转学习测试（与ASD患者表现出损伤的测试类似），利培酮（0.125毫克）和M100907（0.01毫克和0.1毫克）都改善了BTBR小鼠的逆转学习。利培酮（0.125毫克）损害了B6小鼠的逆转学习。概率逆转学习表现的改善是由于治疗增强了对新的正确选择模式的维持。因为利培酮会导致不良副作用，所以使用特定的5 - HT2A受体拮抗剂进行治疗可能会改善ASD患者的认知灵活性，同时也将不良副作用降至最低。
Restricted interests and repetitive behaviors in autism can lead to an ‘insistence on sameness’ for routines and decision-making. The ability to adapt choice patterns when external contingencies change is commonly referred to as cognitive flexibility. To date, there are limited options for treating cognitive inflexibility in autism. Risperidone, an atypical antipsychotic, is approved to treat irritability in autism, but less is known of whether it is effective in treating cognitive inflexibility. Risperidone acts at multiple receptors although only actions at a subset of these receptors may be beneficial for cognitive flexibility. 5HT2A receptor blockade represents one pharmacological action of risperidone. Rodent studies have shown that 5HT2A receptor antagonists improve attention and cognitive flexibility. The present studies investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved cognitive flexibility in the BTBR mouse model of autism. The BTBR mouse compared to C57BL/6J (B6) mice exhibit a deficit in reversing learned choice patterns comparable to that in individuals with autism. The present experiments used a two-choice probabilistic reversal learning test in which the ‘correct’ choice was reinforced on 80% of trials and the ‘incorrect’ choice reinforced on 20% of trials. After initial acquisition, the contingencies were reversed. Both risperidone and M100907 improved probabilistic reversal learning performance in BTBR mice. The same treatments did not improve reversal learning in B6 mice. Because risperidone can often lead to unwanted side effects, treatment with a 5HT2A receptor antagonist may offer an alternative for improving cognitive flexibility in individuals with autism. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating ‘higher-order’ RRBs, e.g. cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present studies investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist improved probabilistic reversal learning performance in the BTBR T+ tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects.
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