Drug Treatment of Ethanol Seeking in Rat and Monkey

大鼠和猴子乙醇寻求的药物治疗

• 批准号: 6744813
• 负责人: CRISTINE L CZACHOWSKI
• 金额: $ 22.48万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744813
• 关键词: GABA receptor; Macaca fascicularis; acamprosate; alcoholism /alcohol abuse chemotherapy; behavioral /social science research tag; disease /disorder model; ethanol; laboratory rat; model design /development; naltrexone; nonhuman therapy evaluation; operant conditionings; psychological models; receptor expression; reinforcer; substance abuse related behavior

DESCRIPTION (provided by applicant): To identify drugs that are likely to be efficacious at decreasing ethanol abuse, are specific to ethanol, and do not alter behaviors motivated by other reinforcing substances, animal models that closely approximate the human condition are necessary. This project proposes the use of an operant behavioral paradigm that allows for pharmacologically relevant levels of ethanol self-administration, that procedurally separates reinforcer-seeking from reinforcer drinking, and that uses two species of animals (rats and monkeys) in varying stages of ethanol experience. Experience will range from single daily drinking bouts (rats), to abusive consumption (monkeys), to ethanol-dependence (rats). The overall goal of this project is to develop and expand the behavioral paradigm that separately measures reinforcer-seeking and reinforcer consumption to test putative pharmacotherapies for the treatment of alcohol abuse with across-species studies. Three approaches will be utilized: 1) nondependent rats with daily, limited access to sucrose or ethanol, 2) ethanol-dependent rats made dependent in inhalation vapor chambers and tested in operant chambers, and 3) heavy ethanol-drinking monkeys with extended daily access to ethanol. Selectivity for ethanol will be determined by using a sweetened fluid as a control for drug effects on other types of reinforcer-motivated behaviors. Also, since the GABA(A) system has been implicated in the reinforcing and behavioral effects of ethanol, GABA(A) receptor ligands will be tested in this model. The profile of GABA(A) modulatory effects will be compared to the effects of two current pharmacotherapies (naltrexone and acamprosate). A "successful pharmacotherapy" will decrease ethanol-seeking behavior and will be selective for ethanol with little to no effect on reinforced responding for the control fluid. Overall, the project allows for the comparison between dependent and nondependent subjects undergoing similar treatments, and the comparison between rats and monkeys in one laboratory. This project responds to 3 of the 5 areas of interest requested in the RFA: testing drugs with known pharmacological properties for therapeutic efficacy, developing a new animal model with high predictive validity, and further research on drugs currently used for the treatment of alcohol abuse.

描述（由申请人提供）： 为了鉴定可能有效减少乙醇滥用的药物，特定于乙醇，并且不会改变其他增强物质动机所激发的行为，因此需要密切近似人类状况的动物模型。该项目提出了使用操作范围的行为范式，该范式允许在药理学上相关的乙醇自我给药水平，从而将寻求增强剂寻求增强剂与增强剂饮酒分开，并在不同的乙醇经验的阶段使用两种动物（大鼠和猴子）。经验的范围从每天的每日饮酒（大鼠）到虐待消费（猴子），再到乙醇依赖（大鼠）。该项目的总体目标是开发和扩展行为范式，该行为范式分别测量寻求增强剂和增强剂的消费，以测试假定的药物治疗，以通过各种各样的研究来治疗酒精滥用。将使用三种方法：1）非依赖性大鼠，每天有限，可以使用蔗糖或乙醇，2）依赖于乙醇的大鼠依赖于吸入蒸气室并在操作室中进行了测试，以及3）重量的乙醇饮用的猴子，每天都可以使用乙醇。乙醇的选择性将通过使用甜味的液体作为对其他类型的增强动力动机行为的影响来确定的。同样，由于GABA（A）系统已与乙醇的增强和行为效应有关，因此将在该模型中测试GABA（A）受体配体。将GABA（a）调节作用的特征与两种当前药物疗法（纳曲酮和丙型苯甲酸酯）的作用进行比较。 “成功的药物疗法”将降低寻求乙醇的行为，并且对乙醇有选择性，而对对照液的加强反应几乎没有影响。总体而言，该项目允许进行类似治疗方法的依赖和非依赖性受试者与一个实验室中大鼠和猴子之间的比较。该项目对RFA中要求的5个感兴趣领域中的3个做出了反应：具有已知药理特性的治疗功效的药物，开发了具有高预测有效性的新动物模型，以及对目前用于治疗酒精滥用的药物的进一步研究。