DEVELOPMENTAL EFFECTS OF METHLENEDIOXYMETHAMPHETAMINE

3,4-亚甲基二氧甲基苯丙胺（MDMA）是一种苯丙胺类似物，具有兴奋和致幻性质。在最近完成的初步实验中，我们已经确定了MDMA暴露后的神经行为影响。具体来说，新生儿服用MDMA（类似于人类子宫发育后期）会导致空间和顺序水迷宫学习和记忆的长期缺陷。产后11-20天MDMA治疗效果最大，产后1-10天效果较小。在上次提交后完成的后续实验中，我们在产仔间设计中重复了这些效应，并表明这些效应不是营养不良或在发育关键阶段发生的盐注射应激的结果。本提案的主要重点是描述在发育性MDMA暴露后学习和记忆被破坏的那些方面，并确定与这些影响相关的内分泌变化。为实现这一目标，将调查以下具体目标：（la）使用食欲（奥尔顿迷宫）和厌恶性动机（莫里斯迷宫的工作记忆版本）两种方法验证MDMA暴露后莫里斯水迷宫缺陷是由工作记忆中断引起的假设；（lb）对暴露于MDMA的新生大鼠在两个兴趣暴露阶段进行药代动力学研究，以确定大脑或血浆药物浓度是否存在发育差异，这可能解释MDMA的缺陷我们发现了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，确定诱导的认知缺陷的发病时间依赖性和长期影响。(3)通过血浆皮质酮和ACTH或下丘脑CRF的变化，确定成人认知效应是否与HPA轴的改变有关；或者通过在高水平迷宫中测量的恐惧程度的变化（不受运动活动水平变化的影响）。此外，我们将在Morris迷宫的干扰线索测试中确定注意力的改变是否有助于学习和记忆的改变。修订后的应用程序的变化包括在所有行为实验、药代动力学和内分泌实验中增加多个剂量组，取消单胺测定，并减少NMDA和NE受体结合的工作范围。扩展的剂量反应实验（包括对交叉任务效应的平衡）将是同类实验中首次证明发育性MDMA暴露会导致长期学习和记忆障碍。这些数据将有助于确定产前使用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.