Dopamine supersensitivity following chronic anti-dopaminergic treatment

长期抗多巴胺能治疗后的多巴胺超敏反应

• 批准号: 355923-2008
• 负责人: Samaha, AnneNoel
• 金额: $ 1.82万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527959
• 关键词: Dopamine; supersensitivity; following; chronic; anti

The dopamine (DA) system is critical for normal, everyday behaviours including eating, procreation and movement, but abnormal DA function is linked to a number of psychiatric disorders including psychosis and drug addiction. The most widely-used animal model of DA hyperactivity involves repeated stimulation of the DA system via administration of DA agonists (e.g., amphetamine) and this model has helped researchers to better understand DA function under normal and abnormal conditions. However, chronic suppression of the DA system (for example, via blockade of DA D2/3 receptors) also induces a DA hyperactive state. This alternate model of DA supersensitivity is an ideal tool to further our understanding of the DA system and its function. However, little is known about the long-term behavioural consequences of chronic DA receptor blockade or about the neurobiological processes involved in the induction of DA supersensitivity under these conditions. The primary goal of the proposed research, therefore, is to use animal models to determine the effects of chronic DA D2/3 receptor blockade on DA-dependent behaviours and to explore potential underlying mechanisms. This will be achieved by treating rats with the DA D2/3 receptor antagonist haloperidol and measuring their behavioural response in commonly-used tests of DA function, including psychomotor sensitization, intravenous drug self-administration and operant responding for conditioned reward. Prior research suggests that increased activity within a specific population of neurons that express the neuropeptide enkephalin and form the striatopallidal pathway might be a common mechanism underlying the ability of either DA agonists or DA D2/3 receptor antagonists to induce a DA supersensitive state. Therefore, I will determine whether the effects of haloperidol treatment on the DA-dependent behaviour mentioned above involve increased activity within the enkephalin/striatopallidal pathway. As such, these results will increase our basic understanding of the functions subserved by the DA system and allow us to better predict outcome when DA function is abnormal.

多巴胺 (DA) 系统对于正常的日常行为（包括饮食、生育和运动）至关重要，但异常的 DA 功能与许多精神疾病有关，包括精神病和毒瘾。最广泛使用的 DA 过度活跃动物模型涉及通过给予 DA 激动剂（例如安非他明）重复刺激 DA 系统，该模型帮助研究人员更好地了解正常和异常条件下的 DA 功能。然而，长期抑制 DA 系统（例如，通过阻断 DA D2/3 受体）也会诱发 DA 过度活跃状态。这种 DA 超敏感性的替代模型是进一步了解 DA 系统及其功能的理想工具。然而，人们对慢性 DA 受体阻断的长期行为后果或在这些条件下诱导 DA 超敏感性所涉及的神经生物学过程知之甚少。因此，本研究的主要目标是利用动物模型来确定长期 DA D2/3 受体阻断对 DA 依赖性行为的影响，并探索潜在的潜在机制。这将通过用 DA D2/3 受体拮抗剂氟哌啶醇治疗大鼠并在常用的 DA 功能测试中测量其行为反应来实现，包括精神运动敏化、静脉内药物自我给药和条件奖励的操作反应。先前的研究表明，表达神经肽脑啡肽并形成纹状体苍白球通路的特定神经元群内的活动增加可能是 DA 激动剂或 DA D2/3 受体拮抗剂诱导 DA 超敏感状态的能力的常见机制。因此，我将确定氟哌啶醇治疗对上述 DA 依赖性行为的影响是否涉及脑啡肽/纹状体苍白球通路内活性的增加。因此，这些结果将增加我们对 DA 系统所支持的功能的基本了解，并使我们能够更好地预测 DA 功能异常时的结果。