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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：亚甲基二氧甲基苯丙胺或摇头丸是一种被广泛滥用的精神活性药物，主要通过调节5-羟色胺转运体的SERT功能和脑内5-羟色胺的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温和的精神运动兴奋剂，据报道，这种效应是由多巴胺能活动介导的。我们先前证明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将占据体内的DAT，这一点从DAT结合潜力的降低可见一斑。方法：在恒河猴(n=5)中，我们用PET成像和DAT配体(11C)CFT来测量DAT结合电位。进行超过60min的PET成像，在纹状体和小脑上绘制感兴趣区，并使用SSRT方法计算结合电位。在产生基础DAT结合电位后，静脉注射MDMA(1.5 mg/kg)，并在注射后1h重复成像。结果：与预期相反，急性剂量MDMA后，用(11C)CFT测得的DAT结合潜力持续高于基准值121%(n=5)。肌肉注射MDMA和DAT配体(11C)阿托品产生不一致的变化，证实了我们之前的发现，即冰毒效应对给药途径和时间敏感。结论：这些意想不到的发现可能归因于冰毒的神经化学特性或技术原因。MDMA可以显著改变DAT调节机制以增加DAT的可用性，或者，MDMA阻断纹状体SERT可以通过(11C)CFT阻止SERT占据以增加DAT的PET配体的可用性。风险分析表明，与成年后开始吸毒相比，早期吸毒导致对酒精、尼古丁、可卡因、阿片类药物和MDMA成瘾的患病率要高得多。我们对MDMA(3，4-亚甲基二氧基甲基苯丙胺，摇头丸)的关注是由于最近年轻人中使用的激增以及对伤害的认识的下降。我们探索了一种假设，即大脑发育期间接触MDMA通过改变指定为轴突引导分子(AGM)的基因的表达来改变正常神经发育的轨迹。动态平衡是神经发育、神经发生和神经适应的关键。方法：青春期小鼠14只，成年小鼠14只，连续6天给予小剂量MDMA(3 mg/kg)或生理盐水，每天测定其活动能力。实时定量聚合酶链式反应检测了死后脑区与MDMA效应有关的22个基因的mRNA表达。结果：MDMA抑制青春期小鼠的运动活动，增加成年小鼠的活动。与成年小鼠相比，青春期小鼠的运动效应发生得更早，并且下降得更快。在纹状体和海马区，MDMA引起与活动、神经发育和神经适应相关的基因表达的不同变化。结论：MDMA在青春期和成年小鼠的运动活动和基因表达水平上产生了显著的差异，可以想见，这可能是青少年对MDMA诱导的成瘾和认知障碍的更高易感性的原因。这一新的方法可能会阐明这些和其他关键基因在调节MDMA，其他滥用精神刺激药物在青少年中的不良后果中所起的作用。