The reinforcing and discriminative stimulus effects of orally administered MDMA

说明(申请人提供)：(1)-3，4-亚甲基二氧基甲基苯丙胺(摇头丸)是一种常见的滥用药物，仍然是一个公共卫生问题。虽然口服给药是娱乐使用者最常用的给药途径，但关于MDMA的增强效果和主观效果的调查很少使用MDMA口服给药。在一个与人类关系密切的物种中，开发口服MDMA自我给药模型，并更好地了解口服MDMA的主观影响是如何通过神经化学调节的，将显著增强我们开发药物疗法的能力，旨在改善MDMA滥用的临床治疗。为了实现这一目标，我们的第一个目标是通过两个实验来表征口服MDMA对狒狒的相对增强效果。首先，可靠的MDMA口服自我给药将通过一种在以前对狒狒精神活性化合物的研究中取得成功的程序来产生。口服MDMA的浓度-反应函数将与赋形剂、d-苯丙胺和非药物口服增强剂(水果饮料)进行比较。在第二个实验中，选择程序将用于将多种浓度的MDMA与其他增强剂进行比较。这些研究将建立一种方法，用于在非人类灵长类动物身上进行可靠的长期口服MDMA自我给药的实验研究，将确定强化发生的浓度范围，将确定自我给药模式的周期性是否会在几天内发展，并将允许与另一种常见的口服滥用兴奋剂以及首选的非药物口服增强剂进行比较。我们的第二个目标是通过使用多剂量辨别程序来区分低剂量和高剂量口服MDMA对狒狒的辨别性刺激效应和神经化学相关性。通过对训练为区分低剂量或高剂量MDMA的狒狒进行药物替代和拮抗测试，然后当狒狒区分两种剂量时，将研究作为低剂量和高剂量MDMA给药的函数而发生的假定不同的神经化学变化。我们预计，低剂量的MDMA与高剂量的MDMA的区别刺激效应将显著不同，这从每个训练剂量的概括性和拮抗性特征中得到了证明。这些数据对于我们理解神经化学机制在多大程度上反映了主观药物效应，特别是对MDMA来说，将是重要的。我们建议的特点是在控制良好的实验室条件下使用MDMA口服给药途径，并使用多个训练剂量来研究MDMA对狒狒的辨别性刺激效应。我们的建议将产生对MDMA滥用药物疗法的未来发展至关重要的数据，从而有助于我们促进MDMA中毒、过量用药和使用/滥用的治疗的长期目标。

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.