Methamphetamine and neurodevelopment in adolescent and adult mice

甲基苯丙胺与青少年和成年小鼠的神经发育

基本信息

批准号：
8048397
负责人：
Bertha K Madras
金额：
$ 21.69万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048397
关键词：
Acute Adolescence Adolescent Adult Affect Affective Age Alcohols Amphetamines Behavior Behavioral Biological Brain Chronic Cocaine Cognition Data Depressed mood Development Dopamine D1 Receptor Dose Drug usage Ephrin-B3 Exposure to General Population Hippocampus (Brain)Human Image In Vitro Indium Inhalant dose form Laboratories Lead Ligands Link Maps Marijuana Measures Mediator of activation protein Mental Depression Methamphetamine Methamphetamine dependence Morphology Mus Mutant Strains Mice Nicotine Opioid Pharmaceutical Preparations Phase Predisposition Process Proteins Publishing Reporting Research Rewards Risk Saline Shapes Students Synaptic plasticity Testing Wild Type Mouse Withdrawal Youth abstracting addiction axon guidance axonal guidance cohort drug reward drug seeking behavior early onset drug use high risk high school mutant neuroadaptation neurodevelopment neurogenesis novel preference prescription opioid protein expression psychostimulant public education receptor repaired small molecule

项目摘要

DESCRIPTION (provided by applicant): Among psychostimulants, methamphetamine (METH) has one of the highest risks for progression to addiction. Although METH use is declining in the general population, use nevertheless persists among high school students and adults. Onset of use during adolescence significantly increases susceptibility to developing addiction to METH, and to other drugs, compared with initiation of drug use during adulthood. The mechanisms underlying the heightened vulnerability of adolescents to addiction are poorly understood. As the adolescent brain is not fully developed and undergoes extensive changes until the mid-twenties, we postulate that METH (and other drugs) alters the trajectory of normal neurodevelopment. Specifically, we will interrogate the hypothesis that METH will affect expression levels of mRNA encoding proteins critical for neurodevelopment, but these changes will differ in the adolescent and adult brain. Axonal guidance molecules (AGMs) are receptors and ligands that guide neurodevelopment (e.g. axon guidance and pruning), and are vital elements in neuroadaptive processes in the adult brain (neurogenesis, synaptic plasticity, dendritic morphology, axonal repair). Accumulating evidence directly and inferentially links psychostimulants (cocaine, amphetamine, methamphetamine) to modulation of AGM expression. Pilot or published research from our laboratory and others demonstrated that: (a) METH altered mRNA expression levels of specific AGMs in hippocampus and, (b) the indirect METH target, the D1 dopamine receptor, altered mRNA expression of specific AGMs in vitro. The hypothesis, that elevated potential for METH addiction in youth is associated with METH-induced alterations in AGMs in hippocampus during a crucial phase of neurodevelopment, resulting in reduced neurogenesis and enhanced drug reward, will be tested in 3 aims. Aim 1 will compare the effects of repeated exposure to a low fixed dose of METH on AGM mRNA expression in the hippocampus and on conditioned place preference in young adolescent or adult mice. Aim 2 will investigate the hypothesis that METH, acting via AGMs, affects hippocampal neurogenesis differently in adolescent and adult mice. Aim 3 will investigate whether ephrin B3, a regulator of neurogenesis, shapes drug-seeking behavior in mice, by comparing METH drug-seeking in wild-type and in null mutant mice in the two age cohorts. The research will fill a major void in neurodevelopmental processes that conceivably shape vulnerability to addiction in the adolescent brain, and guide parallel research with other drugs that engender heightened addictive potential in adolescents. With the advent of small molecules targeted to AGMs, the research may lead to novel probes to image and map these critical proteins in the course of human neurodevelopment, to new medication targets that may assist in reversing METH addiction, compromised cognition and affective states. The findings will furthermore provide information for public education on the biological risks associated with early drug use. PUBLIC HEALTH RELEVANCE: Young adolescents are at higher risk of becoming addicted to methamphetamine than adults, as they are to other drugs (cocaine, marijuana, opioids, alcohol, nicotine, inhalants), yet the effects of these drugs on brain development is largely unknown. The proposed research will investigate whether METH modifies expression of proteins that are critical for neurodevelopment, research that conceivably will provide new leads for medications and information germane to public education on biological consequences of early initiation of drug use.

描述（由申请人提供）：在心理刺激剂中，甲基苯丙胺（甲基苯丙胺）是成瘾发展的最高风险之一。尽管一般人群中的甲基苯丙胺使用量正在下降，但在高中生和成人中仍然存在使用。与成年期间的药物使用相比，青春期的使用显着提高了对甲基苯丙胺和其他药物的成瘾的敏感性。青少年对成瘾的脆弱性增强的机制知之甚少。由于青春期的大脑没有完全发育，并且在二十多岁之前经历了广泛的变化，因此我们假设甲基苯丙胺（和其他药物）会改变正常神经发育的轨迹。具体而言，我们将询问以下假设：Meth会影响编码对神经发育至关重要的蛋白质的mRNA的表达水平，但是这些变化在青少年和成人大脑中会有所不同。轴突引导分子（AGM）是指导神经发育的受体和配体（例如，轴突引导和修剪），是成人大脑神经适应过程的重要元素（神经发生，突触可变性，树突形式，树突形态，轴突修复）。积累证据直接，推断地将精神刺激剂（可卡因，苯丙胺，甲基苯丙胺）与AGM表达的调节联系起来。试点或已发表的我们的实验室和其他研究表明：（a）METH改变了海马中特异性AGM的mRNA表达水平，（b）间接甲基苯甲酸甲酯靶标D1多巴胺受体，改变了特定AGMS在体外的mRNA表达改变。在神经发育的关键阶段，将在3个目标中测试，在至关重要的神经发育阶段，在至关重要的神经发育阶段，甲基水马诱导的AGMS变化的升高与甲基海马诱导的AGMS改变有关的假说将在3个目标中进行测试。 AIM 1将比较反复暴露于低固定剂量的METH对海马中的AGM mRNA表达以及年轻青少年或成年小鼠的条件地位偏好的影响。 AIM 2将研究以下假设：通过AGMS起作用的甲基在青少年和成年小鼠中影响海马神经发生的情况不同。 AIM 3将通过比较两个年龄群中的野生型和无效突变小鼠中的甲基甲基甲基苯丙胺寻求药物，研究神经发生的调节剂Ephrin B3是否会塑造小鼠寻求药物的行为。这项研究将填补神经发育过程中的主要空隙，可以想象，这可以影响青少年大脑中成瘾的脆弱性，并与其他药物进行了并行的研究，这些研究在青少年中引起了上瘾的潜力。随着针对AGM的小分子的出现，该研究可能导致新的探针在人类神经发育过程中形象和映射这些关键蛋白质，以实现可能有助于逆转MET成瘾，受损的认知和情感状态的新药物靶标。这些发现还将为公共教育提供有关与早期药物使用相关的生物学风险的信息。公共卫生相关性：年轻的青少年对甲基苯丙胺上瘾的风险高于成年人，因为它们是其他药物（可卡因，大麻，阿片类药物，酒精，尼古丁，吸入剂），但这些药物对脑发育的影响在很大程度上尚不清楚。拟议的研究将调查METH修改对神经发育至关重要的蛋白质的表达，可以想象的研究将为药物和信息提供新的潜在客户，以使公共教育对早期使用药物使用的生物学后果。