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: 6890366
• 负责人: CRISTINE L CZACHOWSKI
• 金额: $ 22.31万
• 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/6890366
• 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）： 为了确定可能有效减少乙醇滥用、针对乙醇且不改变其他增强物质激发的行为的药物，需要非常接近人类状况的动物模型。该项目提出使用一种操作性行为范式，该范式允许药理学相关水平的乙醇自我管理，在程序上将强化物寻求与强化物饮用分开，并使用处于不同阶段的乙醇体验的两种动物（大鼠和猴子）。经验范围从每天一次饮酒（老鼠），到滥用消费（猴子），再到乙醇依赖（老鼠）。该项目的总体目标是开发和扩展行为范式，分别测量强化物寻求和强化物消耗，以通过跨物种研究测试治疗酒精滥用的假定药物疗法。将使用三种方法：1）非依赖大鼠每天有限地获取蔗糖或乙醇，2）乙醇依赖大鼠在吸入蒸汽室中产生依赖并在操作室中进行测试，3）大量饮酒的猴子每天延长接触乙醇。乙醇的选择性将通过使用甜味液体作为药物对其他类型的强化物驱动行为的影响的对照来确定。此外，由于 GABA(A) 系统与乙醇的强化和行为效应有关，因此将在此模型中测试 GABA(A) 受体配体。 GABA(A) 调节作用的概况将与两种当前药物疗法（纳曲酮和阿坎酸）的作用进行比较。 “成功的药物疗法”将减少乙醇寻求行为，并且对乙醇具有选择性，而对对照液的强化反应几乎没有影响。总体而言，该项目允许对接受类似治疗的依赖和非依赖受试者进行比较，以及在一个实验室中对大鼠和猴子进行比较。该项目响应了 RFA 要求的 5 个感兴趣领域中的 3 个：测试具有已知药理学特性的药物的治疗功效、开发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进行进一步研究。