Toward understanding dopamine receptor contributions to prediction error and reversal learning in anorexia nervosa

了解多巴胺受体对神经性厌食症预测误差和逆转学习的贡献

• 批准号: 9805065
• 负责人: Guido KW Frank
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805065
• 关键词: Adolescent; Adult; Agonist; American Psychiatric Association; Amisulpride; Anorexia Nervosa; Avoidance Learning; Behavioral; Biological Markers; Body Weight decreased; Brain; Brain imaging; Bromocriptine; Clinical Research; Code; Control Groups; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Eating; Eating Disorders; Exploratory/Developmental Grant; Food; Foundations; Fright; Functional disorder; Funding Mechanisms; Future; Human; Impairment; Individual; Insula of Reil; Intervention; Investigation; Magnetic Resonance; Mental disorders; Neurotransmitter Receptor; Neurotransmitters; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Placebos; Population; Protocols documentation; Relapse; Research; Research Design; Reversal Learning; Rewards; Role; Serotonin; Signal Transduction; Stimulus; Taste Perception; Testing; Ventral Striatum; Weight Gain; Woman; aripiprazole; behavioral response; brain behavior; dopamine system; dopaminergic neuron; effective therapy; food restriction; frontal lobe; improved; learned behavior; mortality; neuroimaging; psychologic; receptor; response; reward circuitry; reward processing

Project Summary/Abstract Anorexia nervosa (AN) is an eating disorder associated with intense fear of weight gain, food refusal, and severe weight loss. AN has the highest mortality rate among the psychiatric disorders; however, little is known about biomarkers, and no medication has been approved for AN. Many individuals only partially recover, and treatment options, especially for the psychological components of the illness, are not very effective, highlighting the need for more effective treatments. Brain reward pathways have a direct impact on the drive to eat, and a variety of neuroimaging studies have suggested altered reward processing in AN. The neurotransmitter dopamine has a central role in the reward circuitry to drive food approach, and the dynamic interplay between dopamine receptor response and food restriction could have implications for the pathophysiology of AN. Dopamine-related brain function has been studied indirectly using functional magnetic resonance brain imaging (fMRI) and tasks that deliver reward stimuli unexpectedly, eliciting the so-called prediction error (PE) response. Research in AN showed repeatedly altered PE processing suggesting altered dopamine circuit function in the disorder. Dopamine and PE response have also been associated with altered reversal learning, which has important treatment implication for AN as reversal learning is impaired in the disorder and modulation of the dopamine system could improve treatment. However, the dopamine receptor mechanisms that underlie altered PE response in AN have not been studied. This could be highly important to develop medication interventions. In this application, we will develop a study protocol and gather pilot data to identify whether specific dopamine D2 challenge drugs can modulate PE response and reversal learning in AN. In Aim 1., we will apply a selective dopamine D2 receptor agonist to test its effects on PE and reversal learning. In Aim 2., we will apply a selective dopamine D2/3 receptor antagonist. We expect that those challenge drugs will lead to opposite brain and behavior response within groups and directly support the involvement of those receptors in PE and reversal learning processing. In Aim 3., we will contrast brain and behavior response across challenge drugs in AN against response in healthy controls to gather pilot data for future investigation. This research will be important to develop neurotransmitter specific pharmacological treatments for AN.

项目总结/摘要 神经性厌食症（AN）是一种饮食失调，与体重增加，食物拒绝， 体重严重下降。AN是精神疾病中死亡率最高的疾病，然而，目前对AN的认识还不多 关于生物标志物，没有药物被批准用于AN。许多人只能部分康复，而且 治疗方案，特别是针对疾病的心理因素，并不是很有效，强调 需要更有效的治疗。 大脑奖励途径对进食的驱动力有直接的影响，各种神经成像研究表明， 提示AN中的奖励处理改变。神经递质多巴胺在奖赏中起着重要作用 驱动食物接近的电路，以及多巴胺受体反应和食物之间的动态相互作用 限制可能对AN的病理生理学有影响。多巴胺相关的大脑功能 间接使用功能性磁共振脑成像（fMRI）和提供奖励的任务进行研究， 刺激，引发所谓的预测误差（PE）反应。在AN的研究反复表明， 改变的PE处理表明在障碍中改变了多巴胺回路功能。多巴胺和PE 反应也与改变的逆转学习有关，这具有重要的治疗意义 对于AN作为逆向学习受损的多巴胺系统的紊乱和调节可以改善 治疗然而，在AN中改变PE反应的基础多巴胺受体机制尚未被证实。 本文研究了这对开发药物干预措施非常重要。 在这项申请中，我们将制定一项研究方案，并收集试点数据，以确定是否有特定的 多巴胺D2激发药物可调节AN的PE反应和逆转学习。在目标1中，我们将应用 选择性多巴胺D2受体激动剂，以测试其对PE和逆转学习的影响。在目标2中，我们将 应用选择性多巴胺D2/3受体拮抗剂。我们预计这些挑战性药物将导致 相反的大脑和行为反应的群体，并直接支持这些受体的参与， PE和反向学习处理。在目标3中，我们将对比大脑和行为对挑战的反应， AN中的药物与健康对照的反应进行比较，以收集试点数据用于未来的研究。这项研究将 重要的是开发神经递质特异性药物治疗AN。