Effects of Clopazine and haloperidol on responding

描述(申请人提供)：背景：酒精滥用在精神分裂症(SCZ)患者中很常见；尽管SCZ的酒精消耗量趋于适度，但它会加剧SCZ的进展。这项建议的总体目标是：(A)开始了解叙利亚金黄地鼠酒精消费的潜在因素，这是一个对药物减少SCZ患者酒精滥用的能力具有很强预测有效性的动物模型，以及(B)表征药物减少SCZ患者酒精消费能力的潜在筛查工具。在自由出入的条件下，仓鼠可以稳定地饮酒，但仓鼠对酒精的偏好和动机还没有得到测试。在SCZ患者和仓鼠中，非典型抗精神病药物氯氮平(CLOZ)显著减少酒精消耗量，但典型抗精神病药物氟哌啶醇(HAL)不能。在目前的提案中，我们将在金黄地鼠中区分药物对偏好的影响(条件性位置偏好；CPP)和奖励的动机(操作性自我管理；OSA)。具体目标：本建议的具体目的是：(1)探讨酒精是否在金黄地鼠中产生剂量依赖的CPP；(2)探讨在CPP范式中，CLOZ而不是HAL是否可以阻断仓鼠对酒精的偏好；(3)确定在OSA范式中，与糖精、水和食物相比，仓鼠是否显示出更高的消费酒精和等卡路里蔗糖的动机；以及(4)确定HAL而不是CLOZ是否会降低OSA范式中金黄地鼠对奖励做出反应的动机。实验方案：目标1：将在仓鼠身上测试对酒精或车辆注射反应的CPP。目的：观察赋形剂、氯氮平、氟哌啶醇对金黄地鼠酒精CPP的影响。目标3：仓鼠将接受训练，首先按固定比例按杠杆按压来管理食物和液体，然后按递进比例按比例测试水、蔗糖、糖精和酒精的最大反应(断点)。目的4：一旦训练仓鼠使用杠杆压榨机获取食物和液体，将测试赋形剂、氯氮平或氟哌啶醇对食物、水、蔗糖、糖精和酒精转折点的影响。意义：尽管金黄仓鼠在SCZ被用作酒精滥用的模型，但这种动物酒精消费的潜在因素还没有完全表征，目标1和目标3将允许我们检查其中的两个因素-对酒精的偏好和动机。研究CLOZ和HAL在这些任务中的作用将有助于我们确定CPP或OSA是药物减少酒精摄入能力的更好筛查，并开始了解CLOZ是以什么方式减少SCZ患者的酒精滥用。 公共卫生相关性：拟议的研究将通过阐明氯氮平的作用，为开发治疗共生精神分裂症和药物滥用的新药物疗法提供基础。氯氮平是一种有效但有毒的药物，用于治疗这些共生疾病。这项研究还将提供有关叙利亚金黄地鼠行为的新信息，这种金黄地鼠已被用来测试抗精神病药物和其他药物减少酒精消费的能力。最后，这项工作将有助于表征一种潜在的筛查工具，以测试药物减少精神分裂症患者酒精消费的能力。

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.