Abused NMDA Antagonists: Effects on Cortical Development

点击翻译按钮获取中文摘要

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.