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

• 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
• 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

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。虽然甲基苯丙胺的使用在一般人群中正在下降，但在高中生和成年人中仍然存在。与成年期开始使用毒品相比，青春期开始使用毒品显著增加了对甲基苯丙胺和其他毒品成瘾的易感性。人们对青少年更容易上瘾的潜在机制知之甚少。由于青少年的大脑尚未完全发育，直到20多岁才经历广泛的变化，我们假设METH（和其他药物）改变了正常神经发育的轨迹。具体来说，我们将询问METH将影响对神经发育至关重要的mRNA编码蛋白质的表达水平的假设，但这些变化在青少年和成人大脑中将有所不同。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，并且是成人脑中神经适应性过程（神经发生、突触可塑性、树突形态、轴突修复）中的重要元素。越来越多的证据表明，精神兴奋剂（可卡因、安非他明、甲基安非他明）与AGM表达的调节有着直接而紧密的联系。我们实验室和其他实验室的初步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）间接METH靶点D1多巴胺受体改变了体外特定AGM的mRNA表达。这一假设，即青年甲基苯丙胺成瘾的可能性升高与神经发育关键阶段海马AGM中甲基苯丙胺诱导的改变相关，导致神经发生减少和药物奖励增强，将在3个目标中进行测试。目的1将比较重复暴露于低固定剂量的METH对年轻青春期或成年小鼠海马AGM mRNA表达和条件性位置偏爱的影响。目的2将探讨METH通过AGM作用于青少年和成年小鼠海马神经发生的不同影响的假设。目的3将通过比较两个年龄组中野生型和无效突变小鼠的METH寻药行为，研究神经发生调节因子ephrin B3是否影响小鼠的寻药行为。这项研究将填补神经发育过程中的一个主要空白，可以想象，这些过程会塑造青少年大脑中成瘾的脆弱性，并指导与其他药物的平行研究，这些药物会提高青少年的成瘾潜力。随着靶向AGM的小分子的出现，该研究可能会导致新的探针在人类神经发育过程中对这些关键蛋白质进行成像和映射，从而有助于逆转METH成瘾，认知和情感状态受损的新药物靶点。研究结果还将为公众教育提供有关早期吸毒相关生物风险的信息。 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，因为他们对其他药物（可卡因，大麻，阿片类药物，酒精，尼古丁，吸入剂）成瘾，但这些药物对大脑发育的影响基本上是未知的。这项拟议的研究将调查METH是否会改变对神经发育至关重要的蛋白质的表达，这项研究将为药物和信息提供新的线索，这些信息与早期开始使用药物的生物学后果有关。