Conditioned avoidance response in the development of new antipsychotics.
Conditioned avoidance response in the development of new antipsychotics.
复制标题
DOI：
10.2174/138161210790170085
复制
发表时间：
2010
影响因子：
3.1
通讯作者：
M. Wadenberg
中科院分区：
文献类型：
--
作者：
M. Wadenberg
精神分裂症表现为阳性/精神病、阴性和认知症状。阳性症状似乎是由于多巴胺中脑边缘过度反应所致，而阴性/认知症状可能相反是由于中皮质多巴胺过低所致。传统的多巴胺D2受体阻滞剂(如氟哌啶醇)对精神病/阳性症状有效，但对阴性/认知症状效果较差。然而，一些D2受体的阻断似乎是治疗精神病症状所必需的。因此，目前的抗精神病药物改进策略包括适度阻断D2受体，或部分D2刺激，结合辅助药理学特性，可能增强：i)D2阻断效果；以及ii)认知功能。也有不直接阻断D2的策略。临床活动通常在动物筛选试验(所谓的动物模型)中进行测试。大鼠条件性回避反应的筛选试验对药物抗精神病活性的检测具有特殊的敏感性，具有较高的预测效度。本综述评估了条件性回避反应试验在当前抗精神病药物开发中作为一种筛选工具的重要性、准确性和用途。研究发现：i)条件性回避反应试验具有很强的地位，在当前的抗精神病药物开发中经常使用，并且通常被认为是用于检测潜在的抗精神病药物活性的可靠的筛选工具，具有很高的预测有效性；ii)在当前的抗精神病药物开发中，条件回避反应试验能够检测在亚治疗性D2受体阻断存在的情况下有助于抗精神病活性的药理学特性，以及检测不具有直接D2阻断特性的化合物的抗精神病活性。
Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.