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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要神经性厌食症 (AN) 是一种饮食失调症，与对体重增加的强烈恐惧、拒绝进食和严重的体重减轻。 AN 在精神疾病中死亡率最高；然而，人们知之甚少关于生物标志物，目前还没有批准治疗 AN 的药物。许多人仅部分康复，并且治疗方案，尤其是针对疾病的心理成分的治疗方案，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欲望有直接影响，各种神经影像学研究表明建议改变 AN 中的奖励处理。神经递质多巴胺在奖励中起着核心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 的病理生理学产生影响。多巴胺相关的大脑功能使用功能性磁共振脑成像 (fMRI) 和提供奖励的任务进行间接研究意外的刺激，引发所谓的预测误差（PE）反应。 AN 的研究反复表明 PE处理的改变表明该疾病中多巴胺回路功能的改变。多巴胺和PE 反应也与逆转学习的改变有关，这具有重要的治疗意义对于 AN，因为逆转学习在疾病中受损，多巴胺系统的调节可以改善治疗。然而，AN 中 PE 反应改变背后的多巴胺受体机制尚未被证实。被研究过。这对于制定药物干预措施非常重要。在此应用中，我们将制定研究方案并收集试点数据，以确定是否有特定的多巴胺 D2 激发药物可以调节 AN 中的 PE 反应和逆转学习。在目标 1. 中，我们将应用一种选择性多巴胺 D2 受体激动剂，用于测试其对 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群体内相反的大脑和行为反应，并直接支持这些受体参与 PE和逆向学习处理。在目标 3 中，我们将对比挑战中的大脑和行为反应 AN 中的药物与健康对照中的反应相比较，以收集试点数据以供将来的研究使用。这项研究将开发针对 AN 的神经递质特异性药物治疗非常重要。