Effects of Clopazine and haloperidol on responding

描述（由申请人提供）：背景：酒精滥用在精神分裂症（SCZ）患者中很常见;尽管SCZ患者的酒精消耗倾向于适度，但它阻碍了SCZ的进展。该提案的总体目标是：（A）开始了解叙利亚金黄仓鼠饮酒的潜在因素，这是一种对药物降低SCZ患者酒精滥用能力具有较强预测有效性的动物模型;（B）表征药物降低SCZ患者酒精消耗能力的潜在筛选工具。仓鼠在自由进入的条件下稳定地饮酒，但仓鼠对酒精的偏好和动机尚未得到测试。在SCZ患者和仓鼠中，非典型抗精神病药物氯氮平（CLOZ）显著降低了饮酒量，而典型抗精神病药物氟哌啶醇（HAL）则没有。在当前的提案中，我们将区分药物对金仓鼠奖励的偏好（条件性位置偏好; CPP）与动机（操作性自我给药; OSA）的影响。具体目标：该提议的具体目的是：（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是否可以阻断CPP范例中对酒精的偏好;（3）确定在OSA范例中，与糖精、水和食物相比，仓鼠是否表现出消耗酒精和等热量蔗糖的更高动机;以及（4）确定HAL而不是CLOZ是否会降低仓鼠在OSA范例中对奖励作出反应的动机。实验方案：目的1：将在仓鼠中检测CPP对酒精或溶媒注射的反应。目的2：将检测溶媒、氯氮平或氟哌啶醇对仓鼠酒精CPP的影响。目标3：仓鼠将接受训练，首先按照固定比例时间表通过挤压给予食物和液体，然后按照渐进比例时间表检测对水、蔗糖、糖精和酒精的最大反应（断点）。目标4：一旦仓鼠接受训练，能够用杠杆按压食物和液体，将检测溶媒、氯氮平或氟哌啶醇对食物、水、蔗糖、糖精和酒精折点的影响。重要性：尽管金黄仓鼠已被用作SCZ中酒精滥用的模型，但该动物中酒精消耗的潜在因素尚未完全表征，目标1和3将使我们能够检查其中两个因素-酒精偏好和动机。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是否是药物减少酒精摄入能力的更好筛选，并开始了解CLOZ以何种方式减少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（一种用于治疗这些并发症的有效但有毒的药物）的作用，为开发治疗精神分裂症和药物滥用并发症的新型药物疗法提供基础。这项研究还将提供有关叙利亚金黄仓鼠行为的新信息，该仓鼠已被用于测试抗精神病药物和其他药物减少饮酒的能力。最后，这项工作将有助于表征一种潜在的筛选工具，以测试药物减少精神分裂症患者饮酒的能力。

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.