The reinforcing and discriminative stimulus effects of orally administered MDMA

描述（由申请人提供）：（1）-3，4-亚甲二氧基甲基苯丙胺（MDMA，摇头丸）是一种常见的滥用药物，仍然是一个公共卫生问题。虽然口服给药途径是娱乐性使用者最常用的途径，但对MDMA的增强功效和主观效应的研究很少使用MDMA的口服给药途径。在与人类密切相关的物种中，开发口服MDMA自我给药模型，并更好地了解口服MDMA的主观效应是如何通过神经化学介导的，将显著增强我们开发旨在改善MDMA滥用临床治疗的药物疗法的能力。为了实现这一目标，我们的第一个目标是在两个实验中描述狒狒口服MDMA的相对强化功效。首先，将使用在狒狒中进行的精神活性化合物先前研究中成功的程序，产生可靠的MDMA口服自我给药。将口服MDMA的浓度-反应函数与溶媒、d-苯丙胺和非药物口服兴奋剂（一种水果饮料）进行比较。在第二个实验中，将使用选择程序比较多种浓度的MDMA与其他兴奋剂。这些研究将建立方法学，通过该方法学，可以在非人灵长类动物中对可靠的长期口服MDMA自我给药进行实验研究，将确定发生强化的浓度范围，将确定自我给药模式是否在几天内形成周期性，并将允许与另一种常见的口服滥用兴奋剂药物以及首选的非药物口服兴奋剂进行比较。我们的第二个目的是区分的歧视性刺激的影响和神经化学相关的低剂量和高剂量的口服MDMA狒狒通过使用多剂量的歧视程序。将在接受过区分低剂量或高剂量MDMA训练的狒狒中，然后在狒狒区分两种剂量时，使用药物替代和拮抗试验，研究作为MDMA给药低剂量和高剂量函数的pupulmonary差异神经化学变化。我们预计，低剂量的MDMA的区别性刺激效应将与高剂量的MDMA的区别性刺激效应显著不同，正如每个训练剂量的泛化和拮抗作用曲线所证明的那样。这些数据对于我们理解神经化学机制在多大程度上反映在主观药物效应中，特别是MDMA的主观药物效应中，将是非常重要的。我们的建议的显着特点是使用的MDMA管理在实验室条件下，狒狒的口服途径，并使用多个培训剂量的MDMA狒狒的歧视性刺激效应的调查。我们的提案将产生对MDMA滥用药物治疗未来发展至关重要的数据，从而有助于我们促进MDMA中毒，过量和使用/滥用治疗的长期目标。

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.