Methamphetamine and neurodevelopment in adolescent and adult mice

描述(申请人提供)：在精神刺激剂中，甲基苯丙胺(冰毒)具有最高的上瘾风险。虽然冰毒在普通人群中的使用率正在下降，但在高中生和成年人中仍然存在。与成年后开始使用毒品相比，青春期开始使用毒品显著增加了对冰毒和其他药物上瘾的易感性。青少年更容易上瘾的机制人们知之甚少。由于青春期的大脑直到二十五岁左右才完全发育，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。具体地说，我们将询问这一假设，即冰毒将影响编码对神经发育至关重要的蛋白质的mRNA的表达水平，但这些变化在青少年和成年人的大脑中将有所不同。轴突引导分子是指导神经发育(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。越来越多的证据直接推论地将精神刺激剂(可卡因、苯丙胺、甲基苯丙胺)与调节AGM的表达联系起来。我们实验室和其他实验室的试点或已发表的研究表明：(A)冰毒改变了海马区特定动员体的mRNA表达水平，(B)间接冰毒靶标，即D1多巴胺受体，在体外改变了特定动员体的mRNA表达。这一假说认为，青少年冰毒成瘾的可能性增加与冰毒在神经发育的关键阶段导致海马区AGMs的变化有关，导致神经发生减少和药物奖励增加，这一假说将在3个目标中进行测试。目的1比较低固定剂量冰毒反复暴露对幼年或成年小鼠海马区AGM基因表达和条件性位置偏爱的影响。目的2将研究冰毒通过AGMS对青春期和成年小鼠海马神经发生有不同影响的假说。目的3将通过比较两个年龄段的野生型和缺失突变小鼠的冰毒寻找行为，来研究神经发生的调节剂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，这些过程可能会塑造青少年大脑对成瘾的脆弱性，并将指导与其他药物的平行研究，这些药物会在青少年中产生更高的成瘾潜力。随着以AGM为靶点的小分子的出现，这项研究可能会带来新的探针，以成像和绘制人类神经发育过程中的这些关键蛋白质，并找到可能有助于逆转冰毒成瘾、认知受损和情感状态的新的药物靶点。这些发现还将为公众教育提供信息，使其了解与早期吸毒有关的生物风险。 与公共卫生相关：与成年人相比，青少年对甲基苯丙胺上瘾的风险更高，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)上瘾的风险也更高，但这些药物对大脑发育的影响在很大程度上是未知的。这项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，这项研究有望为药物治疗提供新的线索，并为公众教育早期开始使用药物的生物学后果提供信息。

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.