The reinforcing and discriminative stimulus effects of orally administered MDMA

描述（由申请人提供）：(1)- 3,4 -亚甲基二氧基甲基苯丙胺（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强化功效和主观效应的研究很少采用口服给药途径。开发一种口服MDMA自我给药模型，以及更好地了解口服MDMA的主观效应是如何在与人类密切相关的物种中通过神经化学介导的，将大大提高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在两个实验中表征口服MDMA在狒狒中的相对强化功效。首先，可靠的口服自我给药MDMA将产生的程序，已在以前的研究中成功的精神活性化合物在狒狒。将口服MDMA的浓度-反应函数与对照剂、d-安非他明和非药物口服强化剂（果汁饮料）进行比较。在第二个实验中，选择程序将用于比较多种浓度的MDMA和其他强化剂。这些研究将建立可靠的、长期口服MDMA自我给药的方法，可以在非人类灵长类动物中进行实验研究，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在几天内发展，并将允许与另一种常用的口服兴奋剂药物进行比较，以及优选的非药物口服强化剂。我们的第二个目标是通过使用多剂量区分程序来区分低剂量和高剂量口服MDMA对狒狒的区别刺激效应和神经化学相关。研究人员将在训练狒狒分辨低剂量或高剂量MDMA的过程中，通过药物替代和拮抗试验，以及当狒狒分辨两种剂量时，对低剂量和高剂量MDMA所产生的神经化学变化进行研究。我们预计，低剂量MDMA的区别性刺激效应将与高剂量MDMA的区别性刺激效应显著不同，这可以从每次训练剂量的泛化和拮抗概况中得到证明。这些数据对于我们理解神经化学机制在多大程度上反映在主观药物效应中，特别是MDMA，将是非常重要的。我们的建议的显著特点是在控制良好的实验室条件下，在狒狒中使用口服MDMA给药途径，并在研究MDMA对狒狒的区别刺激效应时使用多重训练剂量。我们的建议将为MDMA滥用药物治疗的未来发展提供基础数据，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.