Methamphetamine and neurodevelopment in adolescent and adult mice

描述（由申请人提供）：在精神兴奋剂中，甲基苯丙胺（冰毒）具有最高的成瘾风险之一。虽然甲基苯丙胺的使用在一般人群中正在下降，但高中生和成年人仍然使用甲基苯丙胺。与成年期开始吸毒相比，青春期开始吸毒显著增加了对冰毒和其他药物成瘾的易感性。青少年易上瘾的潜在机制尚不清楚。由于青少年的大脑在25岁左右才发育完全，并经历了广泛的变化，我们假设冰毒（和其他药物）改变了正常神经发育的轨迹。具体来说，我们将质疑甲基苯丙胺会影响对神经发育至关重要的mRNA编码蛋白表达水平的假设，但这些变化在青少年和成人大脑中是不同的。轴突引导分子（Axonal guidance molecules, AGMs）是指导神经发育（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。越来越多的证据将精神兴奋剂（可卡因、安非他明、甲基苯丙胺）与AGM表达的调节直接和间接联系起来。我们实验室和其他实验室的试点或已发表的研究表明：(a)甲基苯丙胺改变了海马中特定AGMs的mRNA表达水平，(b)甲基苯丙胺的间接靶点D1多巴胺受体改变了体外特定AGMs的mRNA表达。在神经发育的关键阶段，青少年甲基苯丙胺成瘾的可能性升高与甲基苯丙胺诱导的海马体agm改变有关，从而导致神经发生减少和药物奖励增强，这一假设将在三个目标中进行验证。目的1将比较反复暴露于低固定剂量甲基安非他明对年轻青少年或成年小鼠海马AGM mRNA表达和条件位置偏好的影响。目的2将研究冰毒通过agm作用对青少年和成年小鼠海马神经发生不同影响的假设。目的3将通过比较野生型和零突变小鼠在两个年龄组中的寻药行为，研究神经发生的调节因子ephrin B3是否会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。随着靶向agm的小分子的出现，这项研究可能会导致新的探针来成像和绘制人类神经发育过程中的这些关键蛋白质，以及新的药物靶点，这些靶点可能有助于逆转冰毒成瘾、认知受损和情感状态。研究结果将进一步为公众教育提供有关早期使用药物的生物学风险的信息。

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.