DEVELOPMENTAL EFFECTS OF METHLENEDIOXYMETHAMPHETAMINE

3，4-亚甲二氧基甲基苯丙胺（MDMA）是一种苯丙胺类似物，具有兴奋剂和致幻特性。 在最近完成的初步实验中，我们已经确定了神经行为的影响后，发展MDMA曝光。具体而言，新生儿MDMA给药（类似于人类发育的子宫后期阶段）导致空间和顺序水迷宫学习和记忆的长期缺陷。 最大的影响发生在MDMA处理后的出生后第11-20天，处理后第1-10天的影响较小。 在自上次提交以来完成的后续实验中，我们在窝间设计中复制了这些效应，并表明这些效应不是在发育的关键阶段发生的营养不良或盐水注射应激的结果。 该提案的主要重点是描述在发育中暴露于MDMA后受到干扰的学习和记忆方面的特征，并确定与这些影响相关的内分泌变化。 为实现这一目标，将研究以下具体目标：（la）使用食欲刺激和神经刺激来检验以下假设：在发育性MDMA暴露后，Morris水迷宫中的缺陷是由工作记忆的破坏引起的。（奥尔顿迷宫）和厌恶动机（Morris迷宫的工作记忆版本）方法和（lb）对在两个相关暴露阶段暴露于MDMA的新生大鼠进行药代动力学研究，以确定是否存在可能解释以下情况的药物脑或血浆浓度的发育差异：（2）通过对不同发育阶段的动物进行MDMA处理后的检查，确定诱导的认知缺陷的时间依赖性发作和长期影响。 (3)确定成人认知效应是否与HPA轴变化相关，如血浆皮质酮和ACTH或下丘脑CRF的变化所反映;或通过高架十字迷宫（未受自主活动水平变化的影响）中测量的恐惧变化。 此外，我们将确定是否，在测试中的干扰线索的Morris迷宫，注意力的改变可能有助于学习和记忆的变化。本修订申请中的变更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多个剂量组，取消单胺测定，并缩小NMDA和NE受体结合的工作范围至初步研究。 扩大的剂量反应实验（包括交叉任务效应的平衡）将是此类实验中第一个证明发育中接触MDMA会诱导长期学习和记忆障碍的实验。 这些数据将有助于确定与产前使用摇头丸对大脑和认知发育有关的风险。

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.