Zebrafish behavioural assays to identify genetic mechanisms underlying drug seeking and addiction.

斑马鱼行为分析可识别药物寻求和成瘾的遗传机制。

• 批准号: G1000053/1
• 负责人: Caroline Brennan
• 金额: $ 45.48万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1000053%2F1
• 关键词: Zebrafish; behavioural; assays; identify; genetic

Human studies demonstrate that genetic factors contribute to an individual?s vulnerability to drug dependence but few genetic markers that predict vulnerability have been identified. Nonetheless, recent evidence suggests that tailoring treatment to individual characteristics based on assessment of the small number of available genetic markers improves treatment outcomes. Increasing understanding of genetic contributions to drug seeking behaviour will aid development of new therapies to improve treatment outcomes. Impulsivity and novelty seeking are risk factors for drug dependence; novelty seeking predicts propensity to initiate drug taking, impulsivity is associated with progression to compulsive drug taking and return to drug taking following abstinence (relapse). These are key characteristics of drug addiction with relapse presenting the greatest challenge for treatment. Here we aim to develop assays of impulsivity and novelty seeking in zebrafish and use these to selectively-breed zebrafish lines to identify variations in gene sequence that may contribute to vulnerability to drug addiction. We have previously demonstrated that zebrafish show reward responses to drugs of abuse and we have developed tests of compulsive drug seeking and relapse in zebrafish. Here we use modifications of rodent tests to relate novelty seeking and impulsivity in zebrafish to drug seeking behaviour. Once tests predictive of drug seeking in zebrafish have been developed we will use these to establish fish lines that show altered drug seeking behaviour. As the neurochemical pathways involved in drug seeking are evolutionarily conserved and there is a high degree of sequence and functional homology between zebrafish and mammalian genes, results found in zebrafish can inform human studies. Use of zebrafish for neurobehavioural research represents a great opportunity for reduction of the use of higher order vertebrate species thereby reducing animal suffering. Given the proposed EU directive to include tests for addictive potential in all new drug development programmes, the development of zebrafish lines with heightened sensitivity to drugs of abuse and establishment of suitable assays has the potential to minimise costs, both material and ethical, in drug development programmes.

人类研究表明，遗传因素导致了一个人对药物依赖的易感性？S，但几乎没有发现预测易感性的遗传标记。尽管如此，最近的证据表明，基于对少量可用遗传标记的评估，根据个人特征量身定做治疗可以改善治疗结果。增加对寻求药物行为的遗传贡献的了解将有助于开发新的治疗方法，以改善治疗结果。冲动和寻求新奇是药物依赖的危险因素；寻求新奇预测开始吸毒的倾向，冲动与发展到强制吸毒和戒除(复发)后再次吸毒有关。这些都是吸毒成瘾的关键特征，复发是治疗的最大挑战。在这里，我们的目标是开发斑马鱼的冲动和寻求新奇的测试，并利用这些测试来选择性地培育斑马鱼品系，以确定可能导致易受药物成瘾影响的基因序列的变异。我们之前已经证明，斑马鱼对滥用药物有奖励反应，我们还开发了斑马鱼强制寻求药物和复发的测试。在这里，我们使用改进的啮齿动物测试，将斑马鱼的新奇寻求和冲动与寻求毒品行为联系起来。一旦斑马鱼寻找药物的预测测试被开发出来，我们将利用这些测试来建立显示改变的药物寻找行为的鱼线。由于参与药物寻找的神经化学途径在进化上是保守的，而且斑马鱼和哺乳动物的基因在序列和功能上有很高的同源性，在斑马鱼中发现的结果可以为人类研究提供参考。利用斑马鱼进行神经行为研究是减少使用高级脊椎动物物种的一个很好的机会，从而减少动物的痛苦。鉴于拟议中的欧盟指令将成瘾潜力测试纳入所有新药开发计划，开发对滥用药物高度敏感的斑马鱼品系，并建立适当的检测方法，有可能将药物开发计划的物质和伦理成本降至最低。