Dopamine supersensitivity following chronic anti-dopaminergic treatment

多巴胺（DA）系统对正常的日常行为至关重要，包括饮食、生殖和运动，但DA功能异常与许多精神疾病有关，包括精神病和药物成瘾。最广泛使用的DA亢进动物模型涉及通过给予DA激动剂（如安非他明）反复刺激DA系统，该模型有助于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）也会诱导DA过度活跃状态。这种数据处理超敏感性的替代模型是进一步了解数据处理系统及其功能的理想工具。然而，对于慢性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慢性DA D2/3受体阻断对DA依赖行为的影响，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功能测试中测量它们的行为反应来实现，包括精神运动致敏、静脉注射药物自我给药和条件奖励的操作性反应。先前的研究表明，在表达神经肽脑啡肽并形成纹状体通路的特定神经元群体中，活性增加可能是DA激动剂或DA D2/3受体拮抗剂诱导DA超敏感状态的共同机制。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/纹状体通路活性的增加。因此，这些结果将增加我们对DA系统所服务的功能的基本了解，并使我们能够更好地预测DA功能异常时的结果。

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.