Ventrostriatal Dopamine Release and Reward Motivation in MDD

描述(由申请人提供)：鉴于近年来在治疗情绪障碍方面进展甚微，似乎需要更好地了解情绪障碍的基本神经生物学，才能进一步取得进展。奖赏动机(以及与“奖赏学习”密切相关的概念)是抑郁症的核心神经行为领域。虽然关于奖励动机的神经生物学已经了解了很多，但知识中的重要差距阻碍了基础科学成果的应用，以改进对严重抑郁障碍(MDD)的治疗。健康受试者的奖赏动机与腹纹状体(VST)多巴胺(DA)有关，奖赏动机受损与MDD和快感缺失有关。这些数据提示，MDD患者可能存在VST DA功能障碍，临床表现为快感缺乏。我们的初步数据显示，奖赏动机受损与MDD的诊断、快感缺乏和MDD的持久性有关，并受DA激动剂普拉克索单剂量的调节。我们的初步数据还显示，安非他明诱导的多巴胺释放在MDD患者的VST中很低，特别是对于药物未成熟的患者。然而，目前尚不清楚VST DA释放是否是MDD奖赏动机的一种机制，以及VST DA释放和奖赏动机是否可以特异性地预测针对增加VST DA传递的抗抑郁药物的反应。这个R01将测试VST中DA的释放是否与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多巴胺是如何导致MDD动机低下的。我们建议对MDD患者的VST DA释放(使用神经感受器PET成像)和奖励动机(使用有效的概率奖励任务)进行首次研究。VST DA释放是药物或行为治疗的一个有前景的靶点，因为它对药物和行为探针有反应。为了测试这些特征的临床意义，我们将评估VST DA释放、奖励动机和快感缺失与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，该建议使用核心行为维度(奖励学习)和多个分析单元(分子、电路、行为、自我报告)；建议的分析是维度和范畴的。未服药的MDD患者(n=27)和健康对照(HC)受试者(n=27)将在安非他明前后使用[11C]拉氯必利PET完成VST中DA释放的测试，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，以获得关于DA释放、奖励动机和自我报告的快感缺失作为治疗反应预测因素的概念验证数据。如果VST DA的释放和奖励动机与这种新型靶向治疗的反应有关，它将带头开发一类治疗MDD和以动机低为特征的广泛难以治疗的疾病的新疗法。

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.