Abused Inhalant Actions at GABA and Glutamate Synapses

吸入性溶剂滥用是美国青少年中日益严重的问题，可能导致药物滥用。 其他药物。我们研究的长期目标是更好地了解 这些药物的作用机制，以提供合理的治疗策略， 防止吸入性溶剂滥用。有证据表明吸入溶剂对中枢神经系统的作用 系统（CMS）突触，但在谷氨酸和γ-氨基丁酸的影响的重要性 （GABA）突触仍然未知。一些溶剂（如甲苯）似乎可以增强GABA- 介导的抑制性传递，而另一些似乎通过改变谷氨酸- 介导的兴奋我们实验室的初步结果表明，甲苯可以在两种情况下起作用， 突触的类型和组合效应扰乱了神经元的正常回路功能。的 这项研究将使用大鼠海马脑中特征良好的CA 1神经元回路 切片CA 1回路使用GABA和谷氨酸进行快速单突触传递， GABA和谷氨酸受体的结合可以完全阻断这种反应 对手。具体目的如下：1）确定吸入溶剂是否改变GABA- 介导的传播。2)为了确定溶剂是否改变谷氨酸介导的突触 应答3)探讨了氨基酸溶剂效应的细胞和分子机制 突触电生理记录将与选择性NMDA和AMPA相结合 受体拮抗剂研究溶剂诱导的谷氨酸介导的兴奋性 突触后电位平行研究将确定溶剂诱导效应的程度 对CA 1神经元放电的抑制作用是通过对GABA受体/CI通道的作用实现的。吸入 溶剂可能会产生类似于吸入麻醉剂的效果，我们已经研究过， 在我们的实验室工作了15年。综合起来，结果将允许进行定量比较 药物对谷氨酸和GABA介导的常见滥用溶剂的传播的影响 包括：甲苯、1，1，1-三氯乙烷和三氯乙烯。

Inhaled solvent abuse is a growing problem among U.S. teenagers and may lead to the abuse of other drugs. The long-term goal of our research is to gain a better understanding of the mechanisms of action of these drugs, in order to provide rational strategies for the treatment and prevention of inhaled solvent abuse. Evidence exists for inhaled solvent actions at central nervous system (CMS) synapses, but the importance of effects at glutamate and gamma-aminobutyric acid (GABA) synapses remains unknown. Some solvents (e.g. toluene) appear to enhance GABA- mediated inhibitory transmission while others appear to disrupt CMSfunction by altering glutamate- mediated excitation. Preliminary results from our laboratory indicate that toluene can act at both types of synapses and that combined effects disprupt the normal circuit function of neurons. The proposed research will use the well-characterized CA 1 neuron circuit in rat hippocampal brain slices. The CA 1 circuit uses GABA and glutamate for fast monosynaptic transmission and evoked responses can be completely blocked by a combination of GABA and glutamate receptor antagonists. The specific aims are as follows: 1) To determine whether inhaled solvents alter GABA- mediated transmission. 2) To determine whether solvents alter glutamate-mediated synaptic responses. 3) To investigate the cellular and molecular mechanisms of solvent effects at amino acid synapses. Electrophysiological recordings will be combined with selective NMDA and AMPA receptor antagonists to investigate solvent-induced effects on glutamate-mediated excitatory postsynaptic potentials. Parallel studies will determine the extent to which solvent-induced effects on CA 1 neuron discharge come about via effects on GABA receptor/CI- channels. Inhaled solvents will likely produce effects similar to inhalational anesthetics, which we have studied tor over fifteen years in our laboratory. Taken together, the results will allow a quantitative comparison of drug effects on glutamate and GABA-mediated transmission for commonly abused solvents including: toluene, 1,1,1-trichloroethane andtrichloroethylene.