DEVELOPMENTAL EFFECTS OF METHLENEDIOXYMETHAMPHETAMINE

3，4-亚甲基二氧基甲基苯丙胺(MDMA)是一种苯丙胺类似物，具有兴奋剂和致幻作用。在最近完成的初步实验中，我们已经确定了发育中的MDMA暴露对神经行为的影响。具体地说，新生儿服用MDMA(类似于人类发育的子宫晚期)会导致空间和顺序水迷宫学习和记忆的长期缺陷。MDMA治疗后的影响最大出现在出生后11-20天，治疗后的影响较小在1-10天。在上一次提交后完成的后续实验中，我们在窝间设计中复制了这些效应，并表明这些效应不是营养不良或发育关键阶段注射盐水的压力的结果。这一建议的主要焦点是描述发育中MDMA暴露后学习和记忆受到干扰的那些方面，并确定与这些影响相关的内分泌变化。为此，将研究以下具体目标：(La)检验如下假说，即发育中的MDMA暴露后，Morris水迷宫中的缺陷是由于使用食欲(Olton迷宫)和厌恶动机(工作记忆版本的Morris迷宫)的方法导致工作记忆中断，以及(Lb)在感兴趣的两个暴露阶段对暴露于MDMA的新生大鼠进行药代动力学研究，以确定是否存在脑或血浆药物浓度的发育差异，从而可能解释我们发现的特定阶段的认知缺陷。(2)通过检测MDMA治疗后不同发育阶段的动物，确定所致认知功能障碍的发病时间依赖性和长期效应。(3)确定成人的认知效应是否可能与HPA轴的变化有关，反映在血浆皮质酮和ACTH或下丘脑CRF的变化上；或者与在高架加迷宫中测量的恐惧变化有关(不受运动活动水平变化的影响)。此外，我们将确定，在莫里斯迷宫的分心线索测试中，注意力的变化是否可能有助于学习和记忆的变化。这一修订后的应用中的变化包括在所有行为实验以及药代动力学和内分泌实验中增加了多个剂量组，取消了单胺测定，并缩小了与先导研究结合的NMDA和NE受体的工作范围。扩大的剂量-反应实验(包括对跨任务影响的抵消)将是此类实验中第一次证明发育中的MDMA暴露会导致长期的学习和记忆损害。这些数据将有助于识别产前使用MDMA对大脑和认知发育的相关风险。

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine analog that possesses both stimulant and hallucinogenic properties. In recently completed preliminary experiments we have identified neurobehavioral effects following developmental MDMA exposure. Specifically, neonatal MDMA administration (analogous to late in utero stages of human development) results in long-lasting deficits in spatial and sequential water maze learning and memory. The largest effects occurred after MDMA treatment on postnatal days 11-20, with smaller effects after treatment on days 1-10. In a follow up experiment completed since the last submission, we replicated these effects in a between-litter design and showed that the effects were not the result of undernutrition or saline-injection stress occurring during critical stages of development. The primary focus of this proposal is to characterize those aspects of learning and memory that are disrupted following developmental MDMA exposure and to identify the endocrine changes that are associated with these effects. To accomplish this the following specific aims will be investigated: (la) Test the hypothesis that deficits in the Morris water maze following developmental MDMA exposure result from disruptions in working memory using both appetitive (Olton maze) and aversively motivated (working memory version of the Morris maze) approaches and (lb) conduct pharmacokinetic studies on neonatal rats exposed to MDMA at the two exposure stages of interest to determine if there are developmental differences in brain or plasma concentrations of drug that might explain the stage-specific cognitive deficits we have found. (2) Determine the time-dependent onset and long-term effects of the induced cognitive deficits by examining animals at different developmental stages after treatment with MDMA. (3) Determine if the adult cognitive effects could be associated with HPA axis changes as reflected by alterations in plasma corticosterone and ACTH, or hypothalamic CRF; or by alterations in fearfulness as measured in the elevated plus maze (uncontaminated by changes in locomotor activity levels). Further, we will determine whether, in a test of distracter cues on Morris maze, alterations in attention may contribute to the learning and memory changes. Changes in this revised application include the addition o multiple dose groups to all of the behavioral experiments and to the pharmacokinetic and endocrine experiments, elimination of monoamine determinations, and reducing, the scope of work on NMDA and NE receptor binding to pilot studies. The expanded dose-response experiments (including counter-balancing for cross-task effects) will be the first of their kind to demonstrate that developmental MDMA exposure induces long-term learning and memory impairments. Such data will help identify risks associated with the prenatal use of MDMA on brain and cognitive development.