Effects of Neonatal MDMA on Brain and Behavior

新生儿摇头丸对大脑和行为的影响

• 批准号: 7387432
• 负责人: Charles V Vorhees
• 金额: $ 28.55万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387432
• 关键词: ARHGEF5 gene; Abdominal Cavity; Adolescence; Adrenal Glands; Adrenalectomy; Adult; Affect; Aftercare; Age; Animal Model; Animals; Birth; Brain; Cell Proliferation; Chromosome Pairing; Cognitive; Cognitive deficits; Complex; Control Groups; Corticosterone; Corticotropin; Cues; Cytoplasmic Granules; DLG4 gene; Data; Development; Developmental Process; Dose; Drug Exposure; Elevation; Ensure; Event; Excision; Exposure to; Feedback; Feeling; Glutamate Receptor; Glutamates; Growth; HPSE gene; Health; Hippocampus (Brain); Human; Hypothalamic structure; Immunohistochemistry; Injury; Ketoconazole; Lead; Learning; Length; Life; Long-Term Effects; Mediating; Memory; Memory impairment; Metyrapone; Milk; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neonatal; Neurons; Numbers; Operative Surgical Procedures; Outcome; Output; Pathway interactions; Performance; Personal Satisfaction; Pharmaceutical Preparations; Plasma; Pregnant Women; Prevention; Production; Proliferating; Proteins; Range; Rattus; Relative (related person); Research Personnel; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Sex Behavior; Short-Term Memory; Staging; Staining method; Stains; Standards of Weights and Measures; Stress; Swimming; Synapses; Synapsins; System; Techniques; Testing; Third Pregnancy Trimester; Uncertainty; Water; Weaning; adrenal allograft; base; biological adaptation to stress; brain behavior; critical developmental period; day; design; drug of abuse; ecstasy; experience; granule cell; human NR1 protein; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; member; morris water maze; neurotoxic; partial recovery; postnatal; presynaptic density protein 95; prevent; programs; pup; rapid growth; receptor; reproductive; research study; response; restoration; sex; social; spatial integration; stressor; treatment duration; treatment effect

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.

描述（由申请人提供）：3,4-甲基二甲基甲基苯丙胺（MDMA）滥用是一个严重的健康问题，但对其对大脑的影响知之甚少。我们确定，新生大鼠在P11-20（而不是P1-10）暴露后，施用MDMA（三个月暴露的模型）会导致长期路径整合和空间学习和记忆障碍，同时避免了引起的记忆和工作记忆。新数据表明，暴露的后代改变了CAPON，PSD95，NNOS和NMDA-NR1（NMDA受体复合物的所有成员）的表达。这种处理还会导致5-HT的大幅减少，并持续释放皮质酮（CORT）。 P11-20重叠应力性响应期（SHRP，P4-15）。我们假设在SHRP期间开始的MDMA处理触发了独特的事件级联，从压力响应途径过度激活开始（CRF，ACTH，CORT的释放），但正常的反馈机制无法正常运行。由此产生的长时间释放或与伴随的5-HT减少相结合会导致中枢神经系统组织和长期认知缺陷的变化。检验该假设的具体目的是：（1A）确定MDMA诱导的长期认知和NMDA受体复杂效应的关键时期，使用SHRP之前，之中和之后的治疗间隔以及响应压力的变化。 （1B）将AIM 1A的关键时期与对HPA轴和脑5-HT的短期影响的非关键时期进行比较。 （2）使用涉及肾上腺切除术与肾上腺同素同育的新技术测试HPA轴在长期效应中的作用变化，以暂时中断HPA响应，随后恢复基础Cort功能。 （3）通过使用SSRI预处理阻止MDMA诱导的5-HT减少并测试预防认知缺陷，测试5-HT的参与。 （4）确定变化。在NNOS，NMDA-NR1，PSD-95和CAPON和CAPON及其相关蛋白质中未经行为测试，以确保这些变化不依赖于经验依赖。目前的发展MDMA暴露模型是第一个建立诱导认知缺陷的模型，并且是我们远距离目标的第一步，是最终在大脑发育的其他（早期）阶段（早期）阶段暴露后测试MDMA的影响。