Abused Inhalant Actions at GABA and Glutamate Synapses

描述（由申请人提供）：吸入性溶剂滥用是美国青少年中日益严重的问题，并可能导致其他药物的滥用。我们研究的长期目标是更好地了解这些药物的作用机制，以便为治疗和预防吸入性溶剂滥用提供合理的策略。存在吸入溶剂对中枢神经系统（CMS）突触作用的证据，但对谷氨酸和γ-氨基丁酸（GABA）突触作用的重要性仍不清楚。一些溶剂（如甲苯）似乎增强GABA介导的抑制性传递，而其他溶剂似乎通过改变谷氨酸介导的兴奋来破坏CMS功能。我们实验室的初步结果表明，甲苯可以作用于两种类型的突触，并且联合作用会破坏神经元的正常回路功能。该研究将使用大鼠海马脑片中的CA 1神经元电路。CA 1回路使用GABA和谷氨酸进行快速单突触传递，并且诱发反应可以被GABA和谷氨酸受体拮抗剂的组合完全阻断。具体目的如下：1）确定吸入溶剂是否改变GABA介导的传播。2)确定溶剂是否改变谷氨酸介导的突触反应。3)探讨氨基酸突触溶剂效应的细胞和分子机制。电生理记录将与选择性NMDA和AMPA受体拮抗剂相结合，以研究溶剂诱导的谷氨酸介导的兴奋性突触后电位的影响。平行研究将确定溶剂诱导的对CA 1神经元放电的影响通过对GABA受体/CI通道的影响而产生的程度。吸入溶剂可能会产生类似于吸入麻醉剂的作用，我们已经在实验室研究了15年以上。综上所述，结果将允许定量比较药物对谷氨酸和GABA介导的传输的影响，常见的滥用溶剂包括：甲苯，1，1，1-三氯乙烷和三氯乙烯。

DESCRIPTION (provided by applicant): 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 CMS function 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 for over 15 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 and trichloroethylene.