Reward circuit dysfunction, substance use disorder and schizophrenia: a preclinical fMRI-based connectivity study

奖赏回路功能障碍、物质使用障碍和精神分裂症：基于功能磁共振成像的临床前连通性研究

• 批准号: 9375636
• 负责人: ALAN I GREEN
• 金额: $ 28.35万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375636
• 关键词: Address; Adult; Alcohol or Other Drugs use; Alcohols; Animal Model; Animals; Behavior assessment; Behavioral; Behavioral Assay; Biological Assay; Biological Markers; Brain; Cannabinoids; Cannabis; Clinical; Clinical Research; Cocaine; Data; Deltastab; Development; Evaluation; Face; Formulation; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; General Population; Goals; High Prevalence; Hippocampus (Brain); Image; Investigation; Lesion; Methamphetamine; Modeling; Motivation; National Institute of Drug Abuse; Neonatal; Neurobiology; Nicotine; Oral; Patients; Pharmaceutical Preparations; Population; Psychotic Disorders; Public Health; Publishing; Rattus; Research; Rest; Rewards; Role; Schizophrenia; Self-Administered; Severities; Smoke; Substance Use Disorder; Tetrahydrocannabinol; Translational Research; Withdrawal; Work; base; brain circuitry; brain dysfunction; marijuana use; marijuana use disorder; novel therapeutic intervention; pre-clinical; research study; severe psychiatric disorder; therapy development; translational research program

ABSTRACT Although substance use disorder (SUD) occurs commonly in patients with schizophrenia (SCZ) and dramatically worsens their overall clinical course, the mechanisms underlying their substance use remain unknown, and new treatments to limit their substance use are needed. Our translational research program, using fMRI imaging in patients and in animals, aims to uncover mechanisms that underlie SUDs in patients with SCZ, and to facilitate strategies toward treatment development to limit their substance use. Much of this work is based on our published theoretical neurobiologic formulation suggesting that a dysfunction in the brain reward circuit (BRC) underlies substance use in SCZ, and that substances transiently ameliorate this dysfunction. Our recent study using fMRI resting state functional connectivity in patients with SCZ and cannabis use disorder provided some support for this formulation by showing that these patients have a hypoconnected BRC, which is ameliorated by use of cannabis or ∆9- tetrahydrocannabinol (THC). Unfortunately, previous substance use (which, in SCZ, often begins prior to the first episode) potentially confounds interpretation of our data on BRC function in patients with SCZ. Thus, to further elucidate the potential role of BRC dysfunction in patients with SCZ-SUD, and to facilitate development of new treatments, we have turned to the neonatal ventral hippocampal lesioned (NVHL) rat, an animal model of SCZ that displays a propensity for substance use. In this R21 proposal, we begin to bridge the gap between our clinical studies and our theoretical formulation of the basis of substance use in SCZ through study of fMRI resting state functional connectivity of the BRC in the NVHL rat. In our primary aim, we seek to establish that the adult NVHL rat displays a hypoconnected BRC prior to being exposed to any substances, to provide (unconfounded) translational support that a dysregulated BRC underpins substance use in SCZ. In our secondary aim, we will explore whether: (a) cocaine, known to be preferentially self-administered by the NVHL rat; and (b) THC, shown to modulate the connectivity in patients with SCZ and cannabis use disorder, will ameliorate the dysregulated connectivity in the NVHL rat. If we are able to confirm the aims of this R21 investigation, and thus provide further support for our formulation regarding the basis of substance use in SCZ, in subsequent studies, we can begin to utilize BRC connectivity in the NVHL rat as a translational biomarker to facilitate new treatment development (e.g., as a bioassay), and as a platform for mechanistic and behavioral investigations. Given the severity of SCZ, which is worsened by substance use, this research is of great public health importance.

抽象的 尽管药物使用障碍（SUD）通常发生在精神分裂症患者（SCZ）和 在龙上使他们的整体临床过程恶化，其物质使用的基础机制仍然存在 未知，需要限制其物质使用的新治疗方法。我们的翻译研究计划， 在患者和动物中使用fMRI成像，旨在发现患者肥皂水的机制 使用SCZ，并促进治疗开发的策略以限制其物质使用。其中很多 工作基于我们发表的理论神经生物学公式，表明大脑功能障碍 奖励电路（BRC）是SCZ中物质使用的基础，并且该物质会瞬时改善此事 功能障碍。我们最近在SCZ患者中使用fMRI静止状态功能连通性的研究 大麻使用障碍通过表明这些患者有一个 通过使用大麻或∆9-四氢大麻酚（THC）来改善BRC的异位。 不幸的是，以前的物质使用（在SCZ中，通常在第一集之前开始） 在SCZ患者中，我们对BRC功能的数据的解释混淆。这是为了进一步阐明 BRC功能障碍在SCZ-SUD患者中的潜在作用，并促进新疗法的发展， 我们转向新生儿腹侧海马病变（NVHL）大鼠，这是SCZ的动物模型，该模型 显示物质使用的承诺。在此R21提案中，我们开始弥合临床之间的差距 通过研究fMRI静止状态，研究和我们在SCZ中使用物质使用基础的理论公式 NVHL大鼠中BRC的功能连通性。在我们的主要目标中，我们试图确定成年人 NVHL大鼠在暴露于任何物质之前显示出偏连连接的BRC，以提供（不满意） 转化支持BRC失调的基础底物在SCZ中使用。在我们的次要目标中，我们将 探索是否：（a）可卡因，已知是由NVHL大鼠赋予的优先自我管理的； （b）THC， 显示可调节SCZ和大麻使用障碍患者的连通性，可以改善 NVHL大鼠的连通性失调。如果我们能够确认R21调查的目标，并且 因此，在随后 研究，我们可以开始利用NVHL大鼠中的BRC连接性作为翻译的生物标志物来促进新的 治疗开发（例如，作为生物测定法），作为机械和行为研究的平台。 鉴于SCZ的严重程度被药物使用遗忘了，这项研究具有极大的公共卫生 重要性。