Effects of Clopazine and haloperidol on responding

氯帕嗪和氟哌啶醇对反应的影响

• 批准号: 8060008
• 负责人: Danielle Gulick
• 金额: $ 4.76万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060008
• 关键词: Adverse effects; Agranulocytosis; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Antipsychotic Agents; Behavior; Blood alcohol level measurement; Chronic; Clozapine; Confounding Factors (Epidemiology); Development; Disease; Dose; Drug abuse; Energy Intake; Food; Foundations; General Population; Goals; Haloperidol; Hamsters; High Prevalence; Human; Injection of therapeutic agent; Laboratories; Liquid substance; Measures; Mesocricetus auratus; Modeling; Motivation; Myocarditis; Operant Conditioning; Oral; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Protocols documentation; Research; Rewards; Saccharin; Schedule; Schizophrenia; Screening procedure; Seizures; Self Administration; Sucrose; Taste Perception; Techniques; Testing; Training; Water; Work; alcohol behavior; alcohol effect; alcohol response; alcohol seeking behavior; alcohol use disorder; atypical antipsychotic; behavior test; classical conditioning; conditioning; drinking; novel; novel therapeutics; preference; public health relevance; tool

DESCRIPTION (provided by applicant): Background: Alcohol abuse is common in patients with schizophrenia (SCZ); although alcohol consumption in SCZ tends to be moderate, it worsens the progression of SCZ. The overarching goals of this proposal are: (A) to begin to understand the factors underlying alcohol consumption in the Syrian golden hamster, an animal model with strong predictive validity for the ability of drugs to decrease alcohol abuse in patients with SCZ and (B) to characterize a potential screening tool for the ability of drugs to decrease alcohol consumption in patients with SCZ. The hamster consumes alcohol steadily in free access conditions, but the hamster's preference and motivation for alcohol have not been tested. In patients with SCZ and in the hamster, the atypical antipsychotic clozapine (CLOZ) dramatically decreases alcohol consumption but the typical antipsychotic haloperidol (HAL) does not. In the current proposal, we will differentiate between drug effects on preference (conditioned place preference; CPP) vs. motivation (operant self-administration; OSA) for rewards in the golden hamster. Specific Aims: The specific aims of this proposal are: (1) To explore whether alcohol produces dose-dependent CPP in the hamster; (2) to explore whether CLOZ , but not HAL, can block the preference for alcohol in the CPP paradigm; (3) to determine whether the hamster shows a higher motivation to consume alcohol and isocaloric sucrose, compared to saccharin, water, and food, in an OSA paradigm; and (4) to determine whether HAL, but not CLOZ, will decrease the motivation of the hamster to respond for rewards in the OSA paradigm. Experimental Protocols: Aim 1: CPP in response to alcohol or vehicle injections will be tested in the hamster. Aim 2: The effects of vehicle, clozapine, or haloperidol on alcohol CPP in the hamster will be tested. Aim 3: Hamsters will be trained to administer food and fluids by lever-pressing first on a fixed-ratio schedule, then tested for maximum responding (break point) for water, sucrose, saccharin, and alcohol on a progressive-ratio schedule. Aim 4: Once hamsters are trained to lever press for food and fluids, the effects of vehicle, clozapine, or haloperidol on break points for food, water, sucrose, saccharin, and alcohol will be tested. Significance: Although the golden hamster has been used as a model of alcohol abuse in SCZ, the factors underlying alcohol consumption in this animal have not been fully characterized, and Aims 1 and 3 will allow us to examine two of these factors - preference and motivation for alcohol. Studying the effects of CLOZ and HAL in these tasks will help us to determine whether CPP or OSA is a better screen for the ability of drugs to decrease alcohol intake, and to begin to understand in what manner CLOZ is acting to decrease alcohol abuse in patients with SCZ. PUBLIC HEALTH RELEVANCE: The proposed research will provide a foundation for the development of novel pharmacotherapies for co- occurring schizophrenia and drug abuse by elucidating the actions of clozapine, an effective but toxic medication used to treat these co-occurring disorders. This research will also provide new information about the behavior of the Syrian golden hamster, which has been used to test the ability of antipsychotic drugs and other medications to decrease alcohol consumption. Finally, this work will help to characterize a potential screening tool to test the ability of drugs to decrease alcohol consumption in patients with schizophrenia.

描述（由申请人提供）：背景：精神分裂症患者（SCZ）常见酒精滥用；尽管SCZ中的饮酒趋于中等，但SCZ的进展恶化。该提案的总体目标是：（a）开始了解叙利亚黄金仓鼠的饮酒的因素，叙利亚黄金仓鼠是一种动物模型，该模型具有很强的预测有效性，可用于降低SCZ患者的药物滥用酒精滥用的能力，并（b）表征SCZ患者药物降低酒精消耗能力的潜在筛查工具的能力。仓鼠在自由进入条件下稳步消耗酒精，但仓鼠的偏好和酒精动机尚未进行测试。在SCZ和仓鼠的患者中，非典型抗精神病药（CLOZ）大大降低了饮酒量，但典型的抗精神病药氟哌啶醇（HAL）却没有。在当前的建议中，我们将区分药物对偏好（条件地点偏好； CPP）与动机（操作者自我管理； OSA）的影响，以在金仓鼠中获得奖励。具体目的：该提案的具体目的是：（1）探索酒精是否在仓鼠中产生剂量依赖性CPP； （2）探索CLOZ（而不是HAL）是否可以阻止CPP范式中酒精的偏好； （3）确定仓鼠是否显示出在OSA范式中与糖精，水和食物相比，是否表现出更高的消费酒精和等量合成蔗糖的动机； （4）确定HAL而不是CLOZ是否会减少仓鼠在OSA范式中响应奖励的动机。实验方案：AIM 1：将在仓鼠中测试酒精或媒介物的CPP。 AIM 2：将测试车辆，氯氮平或氟哌啶醇对仓鼠中酒精CPP的影响。 AIM 3：将训练仓鼠通过在固定比例的时间表上杠杆压榨来培训以管理食物和液体，然后在渐进式比例计划下测试水，蔗糖，糖精和酒精的最大响应（断裂点）。 AIM 4：一旦对仓鼠进行了训练以抢购食物和液体，将测试车辆，氯氮平或氟哌啶醇对食物，水，蔗糖，糖精和酒精的休息点的影响。意义：尽管金仓鼠已被用作SCZ中酒精滥用模型，但该动物中饮酒的基础因素尚未得到充分表征，目标1和3将使我们能够检查其中两个因素 - 偏好和饮酒的动机。研究CLOZ和HAL在这些任务中的影响将有助于我们确定CPP或OSA是否是药物减少酒精摄入量的能力的更好筛选，并开始了解CLOZ在SCZ患者中采取什么方式减少酒精滥用的方式。 公共卫生相关性：拟议的研究将通过阐明氯氮平的作用（一种有效但有毒的药物来治疗这些共同疾病的疾病来开发新型药物治疗和滥用药物滥用的新型药物疗法，为治疗这些共同疾病的作用奠定了基础。这项研究还将提供有关叙利亚金仓鼠行为的新信息，该信息已用于测试抗精神病药和其他药物减少酒精消耗的能力。最后，这项工作将有助于表征潜在的筛查工具，以测试药物减少精神分裂症患者饮酒的能力。