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.

项目摘要/摘要 神经性厌食症(AN)是一种进食障碍，与体重增加、拒绝进食和 严重的体重减轻。在精神疾病中，AN的死亡率最高；然而，人们对此知之甚少 关于生物标记物，还没有药物被批准用于治疗。许多人只能部分康复，而且 治疗选择，特别是对疾病的心理部分，并不是很有效，强调 需要更有效的治疗方法。 大脑奖励通路对进食的驱动力有直接影响，各种神经成像研究已经 建议更改的奖励处理。神经递质多巴胺在奖赏中起着核心作用。 驱动食物接近的回路，以及多巴胺受体反应和食物之间的动态相互作用 限制可能会对AN的病理生理学产生影响。多巴胺相关的大脑功能已经 间接使用功能磁共振脑成像(FMRI)和提供奖励的任务进行研究 意外的刺激，引发所谓的预测误差(PE)反应。An的研究反复显示 PE过程的改变表明多巴胺回路功能在该疾病中发生了改变。多巴胺与PE 反应也与改变的反转学习有关，这具有重要的治疗意义 对于AS逆转，学习在紊乱中受损，多巴胺系统的调制可能会改善 治疗。然而，在AN中改变PE反应的多巴胺受体机制并没有 已经研究过了。这对开发药物干预措施可能非常重要。 在此应用程序中，我们将制定研究方案并收集试点数据，以确定具体的 多巴胺D2激发药可调节AN的PE反应和逆转学习。在目标1中，我们将申请 一种选择性的多巴胺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，这些挑战药物将导致 相反的大脑和群体内的行为反应，并直接支持这些受体参与 PE和反转学习处理。在目标3中，我们将对比大脑和行为在不同挑战中的反应 针对健康对照的药物反应收集试点数据，用于未来的研究。这项研究将 重要的是开发针对AN的神经递质特异性药物治疗。