Development of rat models of the effort-related symptoms of depression

描述(由申请人提供)：临床心理学家和精神病学家已经开始强调与努力相关的症状的重要性，如无力、冷漠和疲劳，在严重的抑郁症中。然而，尽管目前有大量的测试可用于在动物模型中评估抗抑郁药物，但广泛使用的任务中没有一项专门关注动物的努力相关功能。在过去的几年里，我们的实验室已经在动物身上建立了行为模型，这些模型有助于评估各种神经递质，如多巴胺(DA)和腺苷在付出努力和与努力相关的选择行为中的作用。大量证据表明，这些对动物的基础研究对于理解人类的努力相关功能障碍具有潜在的相关性。然而，关键是要确定这些程序是否可以导致开发与努力相关的抑郁症症状的新模型。出于这些原因，这项拟议的调查的目标是研究与抑郁症相关的几种情况的能力 诱导大鼠努力相关功能障碍。一组研究将评估低剂量的单胺耗竭剂利血平对涉及努力和与努力相关的选择行为的任务的影响。其他实验将研究它们的行为特征 两种抑郁症的遗传模型(先天无助大鼠和Flinders敏感系大鼠)。最后一组研究将使用努力相关功能的行为模型，评估一种新的抑郁症治疗策略(腺苷A2A拮抗剂)和两种众所周知的药物(安非他酮和氟西汀)的效果。拟议的实验旨在测试将这些程序用作抑郁症和其他障碍的努力相关症状的潜在模型的可行性。 与公共健康相关：由于环境限制或障碍，生物体与食物等重要刺激相分离，因此，受激励的行为往往具有高度的活力、毅力和工作产出。此外，生物体不断地根据成本/收益分析做出与努力相关的决定。在临床文献中，精神病学家和心理学家已经开始强调与能量相关的功能障碍的重要性，如神经痛和疲劳，在严重的抑郁症、帕金森症和其他疾病中。关键是要确定动物程序是否可以导致开发与努力相关的抑郁症症状的新模型。出于这些原因，这项拟议的调查的目标是研究与抑郁症状相关的药理学和遗传学条件在大鼠中诱导努力相关功能障碍的能力。研究与努力相关的过程中涉及的大脑机制至关重要，因为这样的研究提供了关于动机的一个基本方面的信息，还因为它们可能导致疲劳相关疾病的新治疗方法的开发。

DESCRIPTION (provided by applicant): Clinical psychologists and psychiatrists have come to emphasize the importance of effort-related symptoms, such as anergia, apathy, and fatigue, in major depression. Nevertheless, despite the large number of tests that are currently available for the assessment of antidepressant drugs in animal models, none of the widely used tasks is specifically focused upon effort-related functions in animals. Over the last few years, our laboratory has developed behavioral models in animals that are useful for assessing the role of various neurotransmitters, such as dopamine (DA) and adenosine, in the exertion of effort and effort-related choice behavior. Considerable evidence indicates that these basic studies in animals are potentially relevant for understanding effort-related dysfunction in humans. However, it is critical to determine if these procedures can lead to the development of novel models of the effort- related symptoms of depression. For these reasons, the goal of the proposed investigation is to study the ability of several conditions that are related to depression to induce effort-related dysfunctions in rats. One group of studies will assess the effects of low doses of the monoamine-depleting agent reserpine on tasks involving exertion of effort and effort-related choice behavior. Additional experiments will study the behavioral characteristics of two genetic models of depression (Congenitally Helpless Rats; Flinders Sensitive line rats). The final group of studies will assess the effects of a novel treatment strategy for depression (adenosine A2A antagonists) and two well known drugs (bupropion and fluoxetine), using behavioral models of effort-related function. The proposed experiments are designed to test the feasibility of using these procedures as potential models of the effort-related symptoms of depression and other disorders. PUBLIC HEALTH RELEVANCE: Organisms are separated from significant stimuli such as food by environmental constraints or obstacles, and therefore motivated behaviors often are characterized by a high degree of vigor, persistence and work output. Moreover, organisms continually make effort-related decisions based upon cost/benefit analyses. In the clinical literature, psychiatrists and psychologists have come to emphasize the importance of energy-related dysfunctions, such as anergia and fatigue, in major depression, Parkinsonism and other disorders. It is critical to determine if animal procedures can lead to the development of novel models of the effort-related symptoms of depression. For these reasons, the goal of the proposed investigation is to study the ability of pharmacological and genetic conditions that are related to depressive symptoms to induce effort-related dysfunctions in rats. It is vital to study the brain mechanisms that are involved in effort-related processes, because such studies provide information about a fundamental aspect of motivation, and also because they could lead to the development of novel treatments for fatigue-related disorders.