Ventrostriatal Dopamine Release and Reward Motivation in MDD

描述（由申请人提供）：鉴于近年来在情绪障碍治疗方面缺乏进展，为了进一步取得进展，似乎需要更好地了解情绪障碍的基本神经生物学。奖励动机（以及与之密切相关的“奖励学习”结构）是抑郁症的核心神经行为领域。尽管人们对奖励动机的神经生物学已经了解了很多，但知识上的重大空白阻碍了基础科学发现在改善重度抑郁症（MDD）治疗方面的应用。健康受试者的奖励动机涉及腹侧纹状体（VST）多巴胺（DA），奖励动机受损与重度抑郁症和快感缺乏有关。这些数据表明VST - DA功能障碍可能存在于重度抑郁症中，临床表现为快感缺乏。我们的初步数据显示，奖励动机受损与重度抑郁症的诊断、快感缺乏症和重度抑郁症的持续性有关，并可通过单剂量的DA激动剂普拉克索进行调节。我们的初步数据还显示，在MDD的VST中，安非他明诱导的DA释放较低，特别是对于未用药的患者。然而，目前尚不清楚VST DA释放是否是MDD中奖励动机的机制，以及VST DA释放和奖励动机是否可以特异性预测针对增加VST DA传递的抗抑郁药物的反应。这个R01将测试VST中的DA释放是否与MDD的奖励动机和治疗结果有关。我们的方法利用神经受体成像和行为神经科学的进展来了解纹状体DA如何导致重度抑郁症的低动机。我们提出在重度抑郁症患者中首次研究VST DA释放（使用神经受体PET成像）和奖励动机（使用经过验证的概率奖励任务）。VST - DA释放对药物和行为探针有反应，是药物或行为治疗的一个有希望的靶点。为了测试这些特征的临床意义，我们将评估VST DA释放、奖励动机和快感缺乏症与DA D2受体激动剂普拉克索治疗的临床结果的关系，普拉克索已被证明具有抗抑郁特性。与NIMH RDoC临时指南一致，该提案使用了核心行为维度（奖励学习）和多个分析单元（分子、电路、行为、自我报告）；建议的分析是量纲的和分类的。未使用药物的MDD患者（n=27）和健康对照（HC）受试者（n=27）将使用[11C]raclopride PET在安非他明前和后完成VST中DA释放测试，并使用概率奖励任务评估他们的奖励学习。成像后，MDD患者将接受为期6周的普拉克索开放标签治疗，以获得DA释放、奖励动机和自我报告快感缺乏症的概念验证数据，作为治疗反应的预测因素。如果VST DA释放和奖励动机与对这种新型靶向治疗的反应有关，它将率先开发一种新型治疗重度抑郁症和以低动机为特征的广泛的难以治疗的疾病的治疗方法。

DESCRIPTION (provided by applicant): Given the paucity of advances in the treatment of mood disorders in recent years, a better understanding of the basic neurobiology of mood dysfunction seems needed for further progress. Reward motivation (and the closely related construct of "reward learning") is a core neurobehavioral domain that is central to depression. Although much has been learned about the neurobiology of reward motivation, important gaps in knowledge impede the application of basic science findings to improving treatment of major depressive disorder (MDD). Reward motivation in healthy subjects involves ventrostriatal (VST) dopamine (DA), and impaired reward motivation is linked to MDD and anhedonia. These data suggest that VST DA dysfunction might be present in MDD and manifested clinically by anhedonia. Our preliminary data show that impaired reward motivation is related to MDD diagnosis, anhedonia, and persistence of MDD, and is modulated by single doses of the DA agonist pramipexole. Our preliminary data also show that amphetamine-induced DA release is low in the VST in MDD, particularly for drug-naive patients. It remains unclear, however, whether VST DA release is a mechanism of reward motivation in MDD, and whether VST DA release and reward motivation might specifically predict response to antidepressants targeted to increase VST DA transmission. This R01 will test if DA release in the VST is related to reward motivation and treatment outcome in MDD. Our approach capitalizes on advances in neuroreceptor imaging and behavioral neuroscience to learn how striatal DA contributes to low motivation in MDD. We propose the first study of both VST DA release (using neuroreceptor PET imaging) and reward motivation (using a validated probabilistic reward task) in MDD patients. VST DA release is a promising target for drug or behavioral treatments because it responds to drug and behavioral probes. To test the clinical implications of these features, we will assess the relationship of VST DA release, reward motivation, and anhedonia to the clinical outcome of treatment with the DA D2 receptor agonist pramipexole, which has been shown to have antidepressant properties. Consistent with NIMH RDoC interim guidance, this proposal uses a core behavioral dimension (reward learning), and multiple units of analysis (molecules, circuits, behavior, self report); proposed analyses are dimensional and categorical. Drug-naive patients with MDD (n=27) and healthy comparison (HC) subjects (n=27) will complete testing for DA release in the VST using [11C]raclopride PET pre- and post-amphetamine, and they will be assessed for reward learning using a probabilistic reward task. After imaging, MDD patients will be offered 6 weeks of open label treatment with pramipexole to obtain proof-of-concept data on DA release, reward motivation, and self-reported anhedonia as predictors of treatment response. If VST DA release and reward motivation are associated with response to this novel targeted treatment, it would spearhead development of a novel class of treatments for MDD and a broad spectrum of difficult-to-treat conditions characterized by low motivation.