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）：在精神兴奋剂中，甲基苯丙胺 (METH) 是成瘾风险最高的药物之一。尽管普通人群中冰毒的使用量正在下降，但高中生和成年人的使用量仍然存在。与成年期开始吸毒相比，青春期开始吸毒会显着增加对冰毒和其他药物成瘾的可能性。青少年更容易成瘾的机制尚不清楚。由于青少年大脑在二十多岁之前尚未完全发育并经历广泛的变化，因此我们假设冰毒（和其他药物）会改变正常神经发育的轨迹。具体来说，我们将质疑冰毒会影响对神经发育至关重要的 mRNA 编码蛋白的表达水平的假设，但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) 是引导神经发育（例如轴突引导和修剪）的受体和配体，是成人大脑神经适应过程（神经发生、突触可塑性、树突形态、轴突修复）的重要元素。不断积累的证据直接并推论地将精神兴奋剂（可卡因、安非他明、甲基苯丙胺）与 AGM 表达的调节联系起来。我们实验室和其他实验室的试点或已发表的研究表明：(a) METH 改变了海马中特定 AGM 的 mRNA 表达水平，(b) METH 间接靶标 D1 多巴胺受体改变了体外特定 AGM 的 mRNA 表达。该假设认为，青少年冰毒成瘾的可能性增加与神经发育关键阶段冰毒诱导的海马 AGM 改变有关，从而导致神经发生减少和药物奖励增强，该假设将在 3 个目标中进行测试。目标 1 将比较反复暴露于低固定剂量的冰毒对海马 AGM mRNA 表达的影响以及对年轻青少年或成年小鼠的条件性位置偏好的影响。目标 2 将研究以下假设：冰毒通过 AGM 发挥作用，对青少年和成年小鼠的海马神经发生产生不同的影响。目标 3 将通过比较两个年龄组中野生型和无效突变小鼠的 METH 药物寻求行为，研究神经发生调节剂肝配蛋白 B3 是否影响小鼠的药物寻求行为。这项研究将填补神经发育过程中的一个重大空白，这一空白可能会影响青少年大脑对成瘾的脆弱性，并指导与其他药物的平行研究，这些药物会增加青少年的成瘾潜力。随着针对 AGM 的小分子的出现，这项研究可能会产生新的探针，对人类神经发育过程中的这些关键蛋白质进行成像和映射，从而找到可能有助于逆转冰毒成瘾、认知受损和情感状态的新药物靶点。此外，研究结果还将为有关早期吸毒相关生物风险的公众教育提供信息。公共卫生相关性：与成年人相比，青少年对甲基苯丙胺成瘾的风险更高，就像对其他药物（可卡因、大麻、阿片类药物、酒精、尼古丁、吸入剂）一样，但这些药物对大脑发育的影响在很大程度上尚不清楚。拟议的研究将调查冰毒是否会改变对神经发育至关重要的蛋白质的表达，这项研究可能会为药物提供新的线索，并与公众教育有关早期开始吸毒的生物学后果密切相关。