Effects of Neonatal MDMA on Brain and Behavior

描述（由申请人提供）：3，4-亚甲二氧基甲基苯丙胺（MDMA）滥用是一个严重的健康问题，但很少有人知道它对大脑发育的影响。我们确定，新生大鼠给予MDMA（孕晚期暴露模型）导致P11-20（但不是P1-10）暴露后的长期路径整合和空间学习和记忆障碍，同时保留线索和工作记忆。新的数据表明，暴露的后代改变了CAPON，PSD 95，nNOS和NMDA-NR 1（NMDA受体复合物的所有成员）的表达。这种治疗也会导致5-HT的大量减少和皮质酮（CORT）的持续释放。P11-20与SHRP、P4-15的应激低反应期重叠。我们假设，在SHRP期间开始的MDMA治疗触发了一系列独特的事件，这些事件始于应激反应通路的过度激活（CRF，ACTH，CORT的释放），但其中正常的反馈机制无法正确运作。单独或与伴随的5-HT减少相结合的所产生的延长的CORT释放导致CNS组织的变化和长期的认知缺陷。检验这一假设的具体目的是：（1a）使用SHRP之前、期间和之后的治疗间隔确定MDMA诱导的长期认知和NMDA受体复合物效应的关键期以及对应激反应的变化。(1b)比较目标1a的关键期与HPA轴和脑5-HT短期效应的非关键期。(2)使用我们开发的一种新技术测试HPA轴变化在长期效应中的作用，该技术涉及肾上腺切除术联合肾上腺同种异体移植，以暂时中断HPA反应，随后恢复基础CORT功能。(3)通过使用SSRI预处理阻断MDMA诱导的5-HT减少来测试5-HT参与，并测试预防认知缺陷。(4)测定未进行行为学试验的动物中nNOS、NMDA-NR 1、PSD-95和CAPON及相关蛋白的变化，以确保这些变化不依赖于经验。目前的发育MDMA暴露模型是第一个建立认知缺陷诱导的模型，也是我们长期目标的第一步，最终测试在大脑发育的其他（早期）阶段暴露后MDMA的影响。

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.