The reinforcing and discriminative stimulus effects of orally administered MDMA

口服 MDMA 的强化和歧视刺激作用

• 批准号: 7371392
• 负责人: Nancy A. Ator
• 金额: $ 36.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371392
• 关键词: Acute; Amphetamines; Area; Behavioral; Clinical; Clinical Treatment; Complement; Condition; Data; Development; Dextroamphetamine; Discrimination; Dopamine; Dose; Drug abuse; Drug usage; Fruit; Future; Goals; Hallucinogens; Human; Institutes; Intoxication; Intravenous; Investigation; Laboratories; Laboratory Animals; Mediating; Methodology; Modeling; Neurotransmitters; Oral; Oranges; Overdose; Papio; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Probability; Procedures; Psychological reinforcement; Psychotropic Drugs; Public Health; Range; Relative (related person); Reporting; Research; Rodent; Route; Self Administration; Self-Administered; Serotonin; Stimulus; Stimulus Generalization; System; Testing; Training; base; day; drinking; drug discrimination; drug of abuse; ecstasy; experience; improved; insight; neurochemistry; nonhuman primate; pre-clinical; reinforcer; research study; response; stimulant abuse

DESCRIPTION (provided by applicant): (1)-3, 4-methylenedioxymethamphetamine (MDMA, ecstasy) is a common drug of abuse that continues to be a public health concern. While the oral route of administration is the most common route used by recreational users, investigations of the reinforcing efficacy and subjective effects of MDMA have rarely used the oral route of MDMA administration. Development of an oral MDMA self-administration model, and a better understanding of how the subjective effects of orally administered MDMA are neurochemically mediated, in a species closely related to humans would significantly enhance our ability to develop pharmacotherapies intended to improve clinical treatment of MDMA abuse. Toward this goal, our first aim is to characterize the relative reinforcing efficacy of orally available MDMA in baboons in two experiments. First, reliable oral self-administration of MDMA will be engendered using a procedure that has been successful in previous studies of psychoactive compounds in baboons. A concentration-response function of orally available MDMA will be compared to vehicle, to d-amphetamine, and to a non-drug oral reinforcer (a fruit drink). In a second experiment, choice procedures will be used to compare multiple concentrations of MDMA to the other reinforcers. These studies will establish the methodology by which reliable, long-term oral MDMA self-administration can be studied experimentally in a nonhuman primate, will determine the range of concentrations across which reinforcement occurs, will determine whether cyclicity in pattern of self-administration develops across days, and will permit comparison to another commonly orally abused stimulant drug, as well as to a preferred non-drug oral reinforcer. Our second aim is to differentiate the discriminative stimulus effects and the neurochemical correlates of a low and a high dose of orally administered MDMA in baboons by use of multiple-dose discrimination procedures. The putatively differential neurochemical changes that occur as a function of lower and higher doses of MDMA administration will be investigated using drug substitution and antagonism testing in baboons trained to discriminate a low or a high dose of MDMA, and then when the baboons are discriminating both doses. We anticipate the discriminative stimulus effects of a low dose of MDMA will differ significantly from those of a high dose of MDMA, as evidenced by the generalization and antagonism profiles for each training dose. These data will be important to our understanding of the extent to which neurochemical mechanisms are mirrored in subjective drug effects in general and for MDMA in particular. The distinguishing features of our proposal are the use of the oral route of MDMA administration under well-controlled laboratory conditions in baboons, and the use of multiple training doses in the investigation of the discriminative stimulus effects of MDMA in baboons. Our proposal will generate data fundamental to the future development of pharmacotherapies for MDMA abuse, thereby contributing to our long-term goal of facilitating treatment of MDMA intoxication, overdose, and use/abuse.

描述（由申请人提供）：（1）-3，4-甲基二甲基甲基苯丙胺（MDMA，狂喜）是一种常见的滥用药物，仍然是公共卫生的关注。虽然口头管理途径是娱乐用户最常见的途径，但对MDMA的增强功效和主观效应的调查很少使用MDMA管理的口服途径。在与人类密切相关的物种中，开发口服MDMA自我给药模型以及对口服施用MDMA的主观作用是神经化学介导的如何更好地理解的，这将显着增强我们开发旨在改善MDMA滥用临床治疗的药物治疗的能力。为了实现这一目标，我们的第一个目标是表征两个实验中口服MDMA在狒狒中的相对增强功效。首先，使用在先前对狒狒精神活性化合物的研究中成功进行MDMA的可靠口服自我给药。将口服MDMA的浓度反应函数与媒介物，D-苯丙胺和非药物口服增强剂（一种果实饮料）进行比较。在第二个实验中，选择程序将用于将多个MDMA与其他增强剂进行比较。这些研究将确定可以在非人类的灵长类动物中实验研究可靠的长期口服MDMA自我管理的方法，将确定发生强化范围的浓度范围天数，并将允许与另一种通常口服滥用的刺激药物以及首选的非药物口服增强剂进行比较。我们的第二个目的是通过使用多剂量歧视程序来区分低剂量和高剂量的口服MDMA和高剂量口服MDMA的神经化学相关性。将使用药物替代和拮抗作用的较低和较高剂量的MDMA给药的函数进行的推定差异性神经化学变化，在接受培训的狒狒中进行抗衡测试，以区分低剂量或高剂量的MDMA，然后当狒狒歧视时， 。我们预计，低剂量的MDMA的歧视性刺激效应将与高剂量的MDMA显着不同，这可以通过每种训练剂量的概括和拮抗作用证明。这些数据对我们对神经化学机制的理解程度至关重要，通常在主观药物作用中，尤其是MDMA。我们提案的显着特征是在狒狒控制良好的实验室条件下使用MDMA给药的口服途径，以及在研究狒狒中MDMA的歧视性刺激作用中使用多种训练剂量。我们的建议将产生数据基础，这是MDMA滥用药物治疗的未来开发基础，从而为我们的长期目标做出了促进治疗MDMA中毒，用药过量和使用/滥用的目标。