Toward a Rat Model of Alcohol Abuse in Schizophrenia

精神分裂症大鼠酒精滥用模型的研究

• 批准号: 7304218
• 负责人: David Thanh Chau
• 金额: $ 6.89万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304218
• 关键词: Address; Adult; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Blood alcohol level measurement; Brain; Breeding; Characteristics; Cocaine; Condition; Data; Development; Exhibits; Frequencies; Future; Goals; Hippocampus (Brain); Investigation; Lesion; Measures; Mediating; Modeling; Morbidity - disease rate; Neonatal; Neurobiology; Numbers; Outcome; Patients; Pharmaceutical Preparations; Physical Dependence; Procedures; Publishing; Rattus; Research; Research Personnel; Research Proposals; Rewards; Rodent; Role; Saccharin; Schizophrenia; Self Administration; Solutions; Standards of Weights and Measures; Sucrose; Symptoms; Techniques; Translating; alcohol use disorder; base; day; drinking; experience; human subject; improved; novel; preference; research study; size

DESCRIPTION (provided by applicant): Alcohol use disorder commonly occurs among patients with schizophrenia and contributes greatly to the morbidity of schizophrenia. Patients with schizophrenia tend to consume modest quantities of alcohol on a regular basis and are less likely to develop alcohol dependence than alcohol abuse, but even this modest use of alcohol dramatically worsens their symptoms and decreases their overall functioning. Green (co- investigator) and colleagues have suggested that such moderate alcohol use may, however, transiently ameliorate a brain reward circuit deficiency that underlies alcohol use disorder in these patients. Unfortunately, available treatments for co-occurring alcohol use disorder in schizophrenia are very limited. This revised R03 proposal seeks to begin a line of research toward the development of such an animal model of alcohol use disorder in schizophrenia, an animal that exhibits characteristics of schizophrenia, and like patients with schizophrenia, also drinks at least moderate amounts of alcohol. To develop this animal model, we propose to use, as a base, a rat with a neonatal ventral hippocampal lesion (the NVHL rat), a well-established animal model of schizophrenia, a rodent that as an adult exhibits requisite characteristics of schizophrenia, demonstrates abnormalities in its brain reward circuit, and, interestingly, has recently been shown to exhibit increased cocaine self-administration. Our preliminary data in a small group of adult NVHL rats also suggest that this rat will voluntarily drink at least moderate amounts of alcohol. This revised research proposal seeks to further probe the potential role of the NVHL rat as an animal model of schizophrenia and comorbid alcohol use disorder. Using free-access conditions, we will: (1) compare the amount and preference of alcohol drinking [and blood alcohol level] in NVHL rats versus sham-operated rats; and (2) compare the size, frequency and temporal distribution of alcohol drinking bouts in NVHL rats versus sham-operated rats. If NVHL rats can be differentiated from sham rats according to these measures, we plan to continue research with NVHL rats in subsequent studies to: (1) explore mechanisms mediating alcohol drinking in these animals (e.g., to address the question of whether alcohol use serves to transiently ameliorate a deficit in brain reward functioning); and (2) screen medications that might be able to decrease alcohol drinking in this rat. Ultimately, we expect to translate the findings from our studies with the NVHL rat into studies involving human subjects, with the long- term goal of this research to find novel medications to treat patients with schizophrenia and alcohol use disorder, and thus to improve the outcome of these patients. Alcohol use disorder occurs commonly among patients with schizophrenia and greatly worsens the overall functioning of these patients. This research seeks to develop an animal model of alcohol use disorder in schizophrenia, an animal model that exhibits schizophrenia-like characteristics as well as increased alcohol drinking. This animal model, when developed, will be used: (1) to elucidate the underlying basis of alcohol use disorder in patients with schizophrenia; and, (2) to develop novel medications to limit alcohol use in these patients.

描述（由申请人提供）：精神分裂症患者中通常发生饮酒障碍，并有助于精神分裂症的发病率。精神分裂症患者倾向于定期食用适度的酒精，并且比酒精滥用饮酒的可能性较小，但是即使对酒精的这种适度使用也会显着恶化其症状并降低其整体功能。绿色（共同研究者）和同事表明，这种适度的酒精使用可能会瞬时改善脑奖励回路缺乏症，这些缺乏症是这些患者中酒精饮用障碍构成的。不幸的是，对于精神分裂症中同时发生的酒精使用障碍的可用治疗非常有限。这项修订后的R03提案旨在开始研究精神分裂症的动物饮酒障碍的动物模型，这是一种表现出精神分裂症特征的动物，并且像精神分裂症患者一样，也至少喝了中等量的酒精。为了开发这种动物模型，我们建议用作基础，具有新生儿腹侧海马病变（NVHL大鼠），这是一种精神分裂症的精神分裂症模型，作为成年人的啮齿动物模型，成年人表现出必需的精神分裂症，对脑奖励的循环表现出了不良的特征，并表现出了人们对脑奖励的异常。我们在一小群成年NVHL大鼠中的初步数据还表明，这只大鼠将自愿喝至少适度的酒精。这项修订的研究建议旨在进一步探讨NVHL大鼠作为精神分裂症和合并症酒精饮酒障碍的动物模型的潜在作用。使用自由访问条件，我们将：（1）比较NVHL大鼠与假手术大鼠中饮酒的数量和偏好； （2）比较NVHL大鼠中酒精饮酒的大小，频率和时间分布与假手术大鼠的大小，频率和时间分布。如果根据这些措施可以将NVHL大鼠与假大鼠区分开，我们计划在随后的研究中继续使用NVHL大鼠进行研究，以：（1）探索介导这些动物中饮酒的机制（例如，解决酒精使用的问题，即是否可以在大脑奖励功能中进行暂时降临的疾病差异）； （2）筛选药物可能能够减少这只大鼠的饮酒。最终，我们希望将NVHL大鼠研究中的研究结果转化为涉及人类受试者的研究，这项研究的长期目标是找到用于治疗精神分裂症和酒精使用障碍患者的新型药物，从而改善这些患者的结果。精神分裂症患者通常发生酒精疾病，并大大恶化这些患者的整体功能。这项研究旨在开发精神分裂症中酒精使用障碍的动物模型，这是一种具有精神分裂症样特征并增加饮酒的动物模型。将使用该动物模型：（1）阐明精神分裂症患者中酒精饮酒障碍的基础； （2）开发新型药物以限制这些患者的酒精使用。