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

人类研究表明，遗传因素有助于个人？人类对药物依赖的脆弱性，但很少有预测脆弱性的遗传标记已被确定。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，针对个体特征进行定制治疗可以改善治疗结果。增加对药物寻求行为的遗传贡献的理解将有助于开发新的疗法以改善治疗结果。冲动性和新奇寻求是药物依赖的危险因素;新奇寻求预测开始吸毒的倾向，冲动性与发展为强迫性吸毒和戒断后重新吸毒（复发）有关。这些是药物成瘾的关键特征，复发是治疗的最大挑战。在这里，我们的目标是开发测试的冲动和新奇的寻求在斑马鱼和使用这些选择性繁殖斑马鱼线，以确定基因序列的变化，可能有助于脆弱性药物成瘾。我们之前已经证明了斑马鱼对滥用药物表现出奖励反应，并且我们已经开发了斑马鱼强迫性药物寻求和复发的测试。在这里，我们使用修改的啮齿动物测试与寻求新奇和冲动的斑马鱼药物寻求行为。一旦开发出预测斑马鱼药物寻求的测试，我们将使用这些来建立显示改变药物寻求行为的鱼线。由于参与药物寻找的神经化学途径在进化上是保守的，并且斑马鱼和哺乳动物基因之间存在高度的序列和功能同源性，因此在斑马鱼中发现的结果可以为人类研究提供信息。使用斑马鱼进行神经行为研究是减少使用高阶脊椎动物物种从而减少动物痛苦的一个很好的机会。鉴于拟议的欧盟指令将成瘾潜力测试纳入所有新药开发计划，开发对滥用药物敏感性较高的斑马鱼品系并建立适当的测定方法，有可能最大限度地降低药物开发计划中的物质和伦理成本。

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.