MDMA ELICITS DIFFERENT BEHAVIORS, GENE EXPRESSION IN ADOLESCENT, ADULT MICE

MDMA 在青少年和成年小鼠中引发不同的行为和基因表达

• 批准号: 8357965
• 负责人: Bertha K Madras
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357965
• 关键词: Acute; Adolescent; Adult; Alcohols; Altropane; Behavior; Binding; Brain; Brain region; Cerebellum; Cocaine; Corpus striatum structure; Development; Dose; Drug usage; Funding; Gene Expression; Generations; Genes; Grant; High Prevalence; Hippocampus (Brain); Hour; Human; Image; Impaired cognition; Injection of therapeutic agent; Intramuscular; Ligands; Macaca mulatta; Measures; Mediating; Methods; Motor Activity; Mus; National Center for Research Resources; New England; Nicotine; Opioid; Perception; Pharmaceutical Preparations; Positron-Emission Tomography; Predisposition; Primates; Principal Investigator; Property; Psychotropic Drugs; Research; Research Infrastructure; Resources; Risk; Role; Route; Saline; Serotonin; Source; Time; United States National Institutes of Health; Youth; addiction; adverse outcome; axonal guidance; base; carbene; cost; dopamine transporter; drug of abuse; early onset drug use; ecstasy; expectation; in vivo; interest; mRNA Expression; neuroadaptation; neurochemistry; neurodevelopment; neurogenesis; nonhuman primate; novel strategies; prevent; psychostimulant; serotonin transporter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AIMS: MDMA methylene-dioxymethamphetamine or ecstasy is a widely abused psychoactive drug, considered to produce its empathic effects primarily by modulating serotonin transporter SERT function and brain serotonin activity. MDMA is also a mild psychomotor stimulant in humans and nonhuman primates, an effect reportedly mediated by dopaminergic activity. We previously demonstrated that MDMA is an effective substrate for the dopamine DAT transporter. Based on these findings, we hypothesized that an acute dose of MDMA would occupy the DAT in vivo, as manifest by reduced DAT binding potential. METHODS: In rhesus monkeys n=5, we used PET imaging and the DAT ligand (11C)CFT to measure DAT binding potential. PET imaging was performed over 60 min, with regions of interest drawn over striatum and cerebellum and binding potential calculated using the SSRT method. Following generation of baseline DAT binding potential, MDMA (1.5 mg/kg was injected intravenously and imaging was repeated 1 hour after drug injection. RESULTS: Contrary to expectations, DAT binding potential measured with (11C)CFT was consistently higher, 121 percent (n=5, than baseline values, following an acute dose of MDMA. Intramuscular MDMA and the DAT ligand (11C)altropane yielded inconsistent changes, confirming our previous findings that METH effects are sensitive to route of administration and time. CONCLUSIONS: These unanticipated findings are conceivably attributable to neurochemical properties of METH or technical reasons. MDMA may alter DAT regulatory mechanisms acutely to increase DAT availability or alternately, MDMA blockade of striatal SERT could prevent SERT occupancy by (11C)CFT to increase PET ligand availability for the DAT.AIMS: The undeveloped adolescent brain is particularly susceptible to addiction. Risk analyses show early onset of drug use results in a much higher prevalence of addiction to alcohol, nicotine, cocaine, opioids, and MDMA, than initiation of drug use in adulthood. Our focus on MDMA (3, 4-methylenedioxymethamphetamine, ecstasy) is driven by a recent surge in use among youth combined with declining perception of harm. We explored the hypothesis that MDMA exposure during brain development alters the trajectory of normal neurodevelopment by modifying expression of genes designated axonal guidance molecules (AGMs). AGMs are critical for neurodevelopment, neurogenesis and neuroadaptation. METHODS: 14 peri-adolescent mice and 14 adult mice were administered either a low dose of MDMA (3 mg/kg) daily for 6 non-sequential days, or saline, with locomotor activity measured daily. Real-time quantitative PCR measured mRNA expression of 22 genes implicated in MDMA effects in post-mortem brain regions. RESULTS: MDMA suppressed locomotor activity in adolescent mice and increased activity in adult mice. Locomotor effects occurred at earlier times and declined faster in adolescent than adult mice. In striatum and hippocampus, MDMA produced different changes in expression of genes implicated in activity, neurodevelopment and neuroadaptation. CONCLUSIONS: MDMA produces marked differences in adolescent and adult mice, in locomotor activity and in gene expression levels, conceivably contributing to the higher susceptibility of adolescents to MDMA-induced addiction and cognitive impairment. This novel approach may clarify the role of these and other critical genes in mediating the heightened adverse consequences of MDMA, other psychostimulant drugs of abuse in adolescents.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目标：MDMA亚甲基二氧基甲基苯丙胺或摇头丸是一种广泛滥用的精神活性药物，被认为主要通过调节5-羟色胺转运体SERT功能和大脑5-羟色胺活性来产生移情作用。MDMA在人类和非人类灵长类动物中也是一种轻度精神兴奋剂，据报道这种作用是由多巴胺能活性介导的。我们以前证明了MDMA是多巴胺DAT转运蛋白的有效底物。基于这些发现，我们假设急性剂量的MDMA会占据体内DAT，表现为DAT结合潜力降低。方法：在恒河猴n=5，我们使用PET成像和DAT配体（11 C）CFT来测量DAT结合潜力。PET成像进行超过60分钟，与感兴趣的区域绘制在纹状体和小脑和结合电位使用SSRT方法计算。 在产生基线DAT结合潜力后，静脉注射MDMA（1.5 mg/kg），并在药物注射后1小时重复成像。研究结果：与预期相反，在急性剂量的MDMA后，用（11 C）CFT测量的DAT结合潜力始终高于基线值121%（n=5）。肌肉注射MDMA和DAT配体（11 C）altropane产生不一致的变化，证实了我们以前的研究结果，即METH的影响是敏感的给药途径和时间。结论：这些意料之外的发现可以归因于METH的神经化学性质或技术原因。MDMA可能会改变DAT监管机制急剧增加DAT的可用性或交替，MDMA的纹状体SERT的封锁可以防止SERT占用（11 C）CFT增加PET配体的可用性为DAT.AIMS：未开发的青少年大脑特别容易成瘾。风险分析表明，早期开始使用药物导致对酒精、尼古丁、可卡因、阿片类药物和MDMA成瘾的流行率远远高于成年后开始使用药物。我们对MDMA（3，4-亚甲二氧基甲基苯丙胺，摇头丸）的关注是由于最近年轻人使用MDMA的激增以及对危害的认识下降。我们探讨了这一假设，即在大脑发育过程中暴露于MDMA通过改变轴突导向分子（AGM）基因的表达来改变正常神经发育的轨迹。AGM对神经发育、神经发生和神经适应至关重要。方法：14只青春期前小鼠和14只成年小鼠每天给予低剂量MDMA（3 mg/kg），连续6天，或给予生理盐水，每天测量自发活动。实时定量PCR测量22个基因的mRNA表达在死后的大脑区域的MDMA的影响。结果：MDMA抑制青春期小鼠的自发活动，增加成年小鼠的活动。运动的影响发生在较早的时间和下降速度比成年小鼠在青少年。在纹状体和海马中，MDMA使与活动、神经发育和神经适应有关的基因表达产生不同的变化。结论：MDMA在青少年和成年小鼠的运动活动和基因表达水平上产生显著差异，可以想象，这是青少年更容易受到MDMA诱导的成瘾和认知障碍的原因。这种新的方法可以澄清这些和其他关键基因在介导MDMA（青少年滥用的其他精神兴奋剂药物）的不良后果加剧中的作用。