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.

摘要 虽然物质使用障碍（SUD）通常发生在精神分裂症（SCZ）患者中， 显著地影响了他们的整体临床过程，但他们使用药物的潜在机制仍然存在， 未知，需要新的治疗方法来限制他们的物质使用。我们的转化研究项目， 在患者和动物中使用fMRI成像，旨在揭示患者SUD的潜在机制， 与SCZ，并促进治疗发展的战略，以限制他们的物质使用。这在很大程度 这项工作是基于我们发表的理论神经生物学公式，表明大脑功能障碍 奖赏回路（BRC）是SCZ中物质使用的基础，物质可以短暂改善这一点 功能障碍我们最近的一项研究使用功能磁共振成像静息状态功能连接在SCZ患者， 大麻使用障碍通过显示这些患者具有 低连接的BRC，其通过使用大麻或β 9-四氢大麻酚（THC）而改善。 不幸的是，以前的物质使用（在SCZ中，通常在第一次发作之前开始）可能 混淆了我们对SCZ患者BRC功能数据的解释。因此，为了进一步阐明 BRC功能障碍在SCZ-SUD患者中的潜在作用，并促进新治疗方法的开发， 我们转向新生的腹侧海马损伤（NVHL）大鼠，这是一种SCZ的动物模型， 有吸毒倾向在这个R21提案中，我们开始弥合我们的临床 研究和我们的理论公式的基础上，物质使用SCZ通过研究功能磁共振成像静息态 NVHL大鼠中BRC的功能连接。在我们的主要目标中，我们寻求建立成年人 NVHL大鼠在暴露于任何物质之前显示低连接BRC，以提供（无混杂） 翻译支持，失调的BRC支持SCZ中的物质使用。在我们的第二个目标中，我们将 探索是否：（a）已知由NVHL大鼠优先自我给药的可卡因;和（B）THC， 显示调节SCZ和大麻使用障碍患者的连接，将改善 NVHL大鼠中的连接失调。如果我们能够确认这次R21调查的目的， 从而为我们关于SCZ物质使用基础的表述提供进一步的支持， 研究中，我们可以开始利用NVHL大鼠中的BRC连接作为翻译生物标志物，以促进新的 治疗开发（例如，作为生物测定），以及作为机制和行为研究的平台。 鉴于SCZ的严重性，这是恶化的物质使用，这项研究是伟大的公共卫生 重要性