Pharmacological Dissociation of Control Circuits in ADHD and Alcohol Dependence

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种严重且普遍的疾病，大约50%的ADHD成人患有合并症物质使用障碍（SUDS）。有影响力的ADHD模型假设了不同的“冷”执行缺陷，包括注意力不集中和注意力不集中，以及“热”执行缺陷，包括过度寻求奖励和无法延迟满足，后者在并发SUDS的ADHD患者中尤为突出。虽然前额叶调节缺陷明显与ADHD和SUDS有关，但前额叶调节并不是一个单一的现象。不同的前额叶回路负责控制注意力，调节注意力和抑制分心，以及控制食欲，调节动机和寻求奖励。此外，已知增强多巴胺和去甲肾上腺素神经传递的兴奋剂可以增强注意力控制，而纳曲酮，阿片受体的拮抗剂，已被证明可以调节动机和寻求奖励。因此，潜在的可分离形式的前额叶调节失败可能与ADHD和SUDS的不同症状群有关，这些回路可能表现出不同的药理调节模式。为了研究这些假设，我们将使用功能磁共振成像（fMRI）研究健康对照者和患有ADHD、酒精依赖以及ADHD合并酒精依赖的成年人对哌醋甲酯、纳曲酮和安慰剂的反应。我们将使用经过充分验证的任务来探测注意力控制和食欲控制回路。我们将使用基于roi的激活分析、功能连接分析和多元模式分类方法分离注意力和食欲控制回路。该项目的目标是描述ADHD和SUDS功能障碍的神经基础，在这些疾病中发展基于生物学的分类，并促进改进的、更有针对性的治疗方法的发展。

DESCRIPTION (provided by applicant): Attention-deficit hyperactivity disorder (ADHD) is a serious and prevalent disorder, and roughly 50% of adults with ADHD have comorbid substance use disorders (SUDS). Influential models of ADHD posit distinct 'cold' executive deficits including inattention and distractibility and 'hot' executive deficits including excess reward- seeking and inability to delay gratification, with the latter especially prominent in ADHD patients who go on to develop comorbid SUDS. Though deficits in prefrontal regulation are clearly implicated in ADHD and SUDS, prefrontal regulation is not a unitary phenomenon. Distinct prefrontal circuits implement attention control, regulation of attention and suppression of distractions, and appetitive control, regulation of motivation and reward seeking. Additionally, stimulants that enhance dopamine and norepinephrine neurotransmission are known to enhance attention control, while naltrexone, an antagonist of opioid receptors, has been shown to modulate motivation and reward seeking. Thus potentially dissociable forms of prefrontal regulatory failure may be associated with distinct clusters of symptoms in ADHD and SUDS, and these circuits may exhibit different patterns of pharmacological modulation. To investigate these hypotheses, we will use fMRI to investigate healthy controls and adults with ADHD, alcohol dependence, and ADHD comorbid with alcohol dependence in response to methylphenidate, naltrexone, and placebo challenge. We will employ well- validated tasks that probe attention control and appetitive control circuits. We will dissociate attention and appetitive control circuits using ROI-based activation analyses, functional connectivity analyses, and multivariate pattern classification methods. This project advances the goals of delineating the neural basis of dysfunction in ADHD and SUDS, developing biologically-based classification in these disorders, and spurring the development of improved, more tailored treatments.