Effects of Neonatal MDMA on Brain and Behavior

描述(申请人提供)：3，4-亚甲基二氧基甲基苯丙胺(MDMA)滥用是一个严重的健康问题，但人们对其对大脑发育的影响知之甚少。我们证实，在P11-20(但不是P1-10)暴露后，给予MDMA(妊娠晚期暴露的模型)的新生大鼠会导致长期的路径整合以及空间学习和记忆障碍，同时保留线索和工作记忆。新数据显示，暴露的后代改变了Capon、PSD95、nNOS和NMDA-NR1(NMDA受体复合体的所有成员)的表达。这种治疗还会导致5-羟色胺的大量减少和皮质酮(CORT)的持续释放。P11-20与应激低反应期(SHRP，P4-15)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，始于应激反应途径(CRF、ACTH、CORT的释放)的过度激活，但其中正常的反馈机制无法正常运行。由此导致的皮质醇释放延长或合并伴随的5-羟色胺减少会导致中枢神经系统组织的改变和长期的认知缺陷。检验这一假设的具体目的是：(1A)确定MDMA诱导的长期认知和NMDA受体复合效应的关键期，使用SHRP之前、期间和之后的治疗间隔以及对应激反应的变化。(1b)比较从目标1a开始的临界期和对HPA轴和大脑5-羟色胺的短期影响的非临界期。(2)用我们开发的肾上腺切除联合同种异体肾上腺移植暂时阻断HPA反应，随后恢复基础皮质功能的新技术，检测HPA轴变化在远期效应中的作用。(3)用SSRI预处理法阻断MDMA诱导的5-羟色胺的降低来检测5-羟色胺的参与，并进行认知功能障碍的预防试验。(4)确定未经行为测试的动物的nNOS、NMDA-NR1、PSD-95和Capon及相关蛋白质的变化，以确保这些变化不是经验依赖的。目前的发育性MDMA暴露模型是第一个建立认知缺陷诱导的模型，也是我们最终测试在大脑发育的其他(早期)阶段暴露后MDMA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.