Abused NMDA Antagonists: Effects on Cortical Development

R21的应用评估了滥用NMDA拮抗剂氯胺酮和右美沙芬通过改变谷氨酸受体的功能和表达，可能对新皮质的发育产生不利影响的假说。在青少年中，滥用抑制NMDA受体的药物，如五氯苯酚、氯胺酮和右美沙芬正在增加。由于NMDA受体在新皮质回路的发育中起关键作用，滥用NMDA拮抗剂有可能永久改变正常感觉处理和认知所需的回路。NMDA拮抗剂可能通过几种方式损害大脑发育：改变神经递质受体的发育性程序性表达，损害轴突和树突的发育，改变皮质地图的精确度，增加神经元的凋亡。拟议的实验使用了一个表征良好的新皮质发育模型，该模型表现出强大的依赖活动的可塑性，即啮齿动物从胡须到桶的路径。三种谷氨酸拮抗剂将接受评估：1)氯胺酮，一种短效解离麻醉剂，阻断NMDAR通道，通常被用作儿童麻醉剂，在俱乐部或狂欢派对场景中被滥用；2)右美沙芬，一种阻断NMDAR通道并被青少年滥用的止咳药；3)MK-801，一种长效NMDAR通道阻滞剂，已证实对大脑发育有影响。具体目的是使用啮齿动物桶形场模型来检验这些NMDA拮抗剂对以下方面的影响：1)躯体感觉图的发展和谷氨酸受体的表达；2)出生后大鼠大脑中的细胞程序性死亡和BDNF的表达；3)经验依赖的皮质可塑性。这些实验将评估桶田的形态发育和可塑性、谷氨酸受体的表达、下游对BDNF和c-fos mRNA表达的影响以及细胞凋亡。根据我们以前的经验，啮齿动物桶模型应该能对这些滥用药物对新皮质发育和可塑性的潜在影响提供一个强大的、高度敏感的评估。

This R21 application evaluates the hypothesis that the abused NMDA antagonists ketamine and dextromethorphan, by altering the function and expression of glutamate receptors, may have detrimental effects on the development of neocortex. Abuse of drugs that inhibit the NMDA receptor, such as PCP, ketamine and dextromethorphan, is increasing among adolescents. Because NMDA receptors play a critical role in the development of neo-cortical circuitry, abuse of NMDA antagonists has the potential to permanently alter the circuitry needed for normal sensory processing and cognition. NMDA antagonists may impair brain development in several ways: altering the developmentally programmed expression of neurotransmitter receptors, impairing the development of axonal and dendritic arbors, changing the precision of cortical maps, and increasing neuronal apoptosis. The proposed experiments use a well-characterized model of neocortical development that exhibits robust activity-dependent plasticity, the rodent whisker to barrel pathway. Three glutamate antagonists will be evaluated: 1) ketamine, a short-acting dissociative anesthetic that blocks the NMDAR channel, commonly used as an anesthetic in children and abused in the Club or rave scene; 2) dextromethorphan, a cough suppressant that blocks the NMDAR channel and is abused by adolescents; 3) MK-801, a longer- acting NMDAR channel blocker with documented effects on brain development. The specific aims use the rodent barrel field model to examine the effects of these NMDA antagonists on: 1) the development of somatosensory maps and the expression of glutamate receptors, 2) programmed cell death and BDNF expression in the postnatal rat brain, 3) experience-dependent cortical plasticity. The experiments will evaluate barrel field morphologic development and plasticity, expression of glutamate receptors, downstream effects on BDNF and c- fos mRNA expression and apoptosis. Based on our previous experience, the rodent barrel field model should provide a powerful, highly sensitive assessment of the potential impact of these abused drugs on neocortical development and plasticity.