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，包括进食、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多动动物模型包括通过给予DA激动剂(如苯丙胺)反复刺激DA系统，该模型帮助研究人员更好地了解正常和异常情况下的DA功能。然而，DA系统的慢性抑制(例如，通过阻断DA D2/3受体)也会诱导DA过度活跃状态。这种DA超敏反应的替代模型是加深我们对DA系统及其功能的理解的理想工具。然而，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超敏反应所涉及的神经生物学过程知之甚少。因此，这项拟议研究的主要目标是使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，并测量它们在常用的DA功能测试中的行为反应，包括精神运动敏感化、静脉给药和对条件奖赏的操作反应，来实现这一点。先前的研究表明，表达神经肽脑啡肽并形成纹状体延髓通路的特定神经元群体内活动增加可能是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依赖行为的影响是否涉及脑啡肽/纹状体皮质激素途径中活动的增加。因此，这些结果将增加我们对DA系统所辅助的功能的基本了解，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.