Abused Inhalant Actions at GABA and Glutamate Synapses

GABA 和谷氨酸突触的滥用吸入行为

• 批准号: 6964848
• 负责人: M. Bruce MacIver
• 金额: $ 23.43万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6964848
• 关键词: AMPA receptors; NMDA receptors; aminoacid; brain electrical activity; central nervous system; electrophysiology; evoked potentials; gamma aminobutyrate; glutamates; hippocampus; inhalation drug abuse; inhibitor /antagonist; laboratory rat; neural transmission; neuroanatomy; neurotoxicology; pharmacokinetics; solvents; synapses; toluene; trichloroethylene

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.

描述（由申请人提供）：吸入溶剂滥用是美国青少年的日益严重的问题，可能导致滥用其他药物。我们研究的长期目标是更好地了解这些药物的作用机制，以便为治疗和预防吸入溶剂滥用提供合理的策略。有证据表明中枢神经系统（CMS）突触的吸入溶剂作用，但是在谷氨酸和γ-氨基丁酸（GABA）突触中作用的重要性仍然未知。一些溶剂（例如甲苯）似乎增强了GABA介导的抑制性传播，而另一些溶剂似乎通过改变谷氨酸介导的激发来破坏CMS功能。我们实验室的初步结果表明，甲苯可以在两种类型的突触中起作用，并且结合效应失去了神经元的正常电路功能。拟议的研究将在大鼠海马脑切片中使用良好的CA 1神经元回路。 CA 1电路使用GABA和谷氨酸进行快速的单突触传播，并且可以通过GABA和谷氨酸受体拮抗剂的组合完全阻断诱发的反应。具体目的如下：1）确定吸入的溶剂是否改变了GABA介导的传播。 2）确定溶剂是否改变了谷氨酸介导的突触反应。 3）研究氨基酸突触上溶剂作用的细胞和分子机制。电生理记录将与选择性NMDA和AMPA受体拮抗剂结合使用，以研究溶剂诱导的对谷氨酸介导的兴奋性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神经元排出的影响通过对GABA受体/CI-通道的影响。吸入溶剂可能会产生类似于吸入麻醉药的作用，我们在实验室学习了15年以上。综上所述，结果将允许对普通滥用溶剂的谷氨酸和GABA介导的传播进行定量比较：甲苯，1,1,1-三氯乙烷和三氯乙烯。