Effects of Neonatal MDMA on Brain and Behavior

描述（由申请人提供）：3,4-亚甲基二氧甲基苯丙胺（MDMA）滥用是一种严重的健康问题，但它对发育中的大脑的影响知之甚少。我们发现，给予MDMA的新生大鼠（妊娠晚期暴露模型）在P11-20（而不是P1-10）暴露后会导致长期路径整合和空间学习记忆障碍，同时保留线索和工作记忆。新的数据显示，暴露的后代改变了CAPON、PSD95、nNOS和NMDA- nr1（所有NMDA受体复合物的成员）的表达。这种治疗也导致5-羟色胺的大量降低和皮质酮（CORT）的持续释放。P11-20与应激低反应期重叠（SHRP, P4-15）。我们假设，在SHRP期间开始的MDMA治疗引发了一系列独特的事件，从过度激活应激反应途径（CRF， ACTH， CORT的释放）开始，但正常的反馈机制无法正常运作。由此产生的单独或联合5-羟色胺减少的延长CORT释放导致中枢神经系统组织的改变和长期认知缺陷。验证这一假设的具体目的是：（1a）在SHRP之前、期间和之后使用治疗间隔确定mdma诱导的长期认知和NMDA受体复合效应的关键时期，以及应激反应的变化。（1b）比较Aim 1a的关键时期与非关键时期对下丘脑轴和脑5-羟色胺的短期影响。(2)利用我们开发的一种新技术，通过肾上腺切除术联合肾上腺异体移植，暂时中断HPA反应，随后恢复基础CORT功能，测试HPA轴变化在长期效应中的作用。(3)采用SSRI预处理阻断mdma诱导的5-HT降低，检测5-HT参与程度，并进行认知缺陷预防试验。(4)确定变更。在nNOS、NMDA-NR1、PSD-95和CAPON及相关蛋白中，未进行行为测试以确保这些变化不依赖于经验。目前的MDMA发育暴露模型是第一个建立认知缺陷诱导的模型，也是我们最终测试MDMA在大脑发育的其他（早期）阶段暴露后的影响的长期目标的第一步。

DESCRIPTION (provided by applicant): 3,4-Methylenedioxymethamphetamine (MDMA) abuse is a serious health problem yet little is known about its effects on developing brain. We established that neonatal rats administered MDMA (a model of 3rd trimester exposure) causes long-term path integration and spatial learning and memory impairments after P11-20 (but not P1-10) exposure, while sparing cued and working memory. New data show that exposed offspring have altered expression of CAPON, PSD95, nNOS, and NMDA-NR1 (all members of the NMDA receptor complex). This treatment also causes large reductions in 5-HT and sustained release of corticosterone (CORT). P11-20 overlaps the stress hyporesponseive period (SHRP, P4-15). We hypothesize that MDMA treatment that begins during the SHRP triggers a unique cascade of events beginning with overactivation of the stress response pathway (release of CRF, ACTH, CORT) but in which normal feedback mechanisms fail to operate correctly. The resulting prolonged CORT release alone or combined with the concomitant 5-HT reductions lead to changes in CNS organization and long-term cognitive deficits. Specific aims to test this hypothesis are: (1a) Determine the critical period for MDMA-induced long-term cognitive and NMDA receptor complex effects using treatment intervals before, during and after the SHRP and for changes in response to stress. (1b) Compare the critical period from Aim 1a with a non-critical period for short-term effects on the HPA axis and brain 5-HT. (2) Test the role of HPA axis changes in the long-term effects using a new technique we developed involving adrenalectomy combined with adrenal alloengraftment to temporarily interrupt HPA responses with later restoration of basal CORT function. (3) Test 5-HT involvement by blocking MDMA-induced 5-HT reduction using SSRI pretreatment and test for prevention of cognitive deficits. (4) Determine changes .in nNOS, NMDA-NR1, PSD-95 and CAPON and related proteins in animals not tested behaviorally to ensure that these changes are not experience-dependent. The present model of developmental MDMA exposure is the first to establish induction of cognitve deficits and is the first step in our long range objective to ultimately test the effects of MDMA after exposure during other (earlier) stages of brain development.