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: 7633484
• 负责人: M. Bruce MacIver
• 金额: $ 3.37万
• 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/7633484
• 关键词: AMPA Receptors; Accounting; Acids; Address; Amino Acids; Amphetamines; Anesthesia procedures; Anesthetics; Animals; Aromatic Hydrocarbons; Behavioral; Brain; Brain Stem; Breathing; Buffers; Calcium; Calcium Channel; Cells; Chemicals; Chromosome Pairing; Class; Cocaine Abuse; Color; Conscious; Cytoplasmic Granules; Dantrolene; Dendrites; Depressed mood; Disinhibition; Disruption; Drug effect disorder; Educational process of instructing; Electrodes; Euphoria; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Fiber; Frequencies; GABA Receptor; GTP-Binding Proteins; Glutamate Receptor; Glutamates; Goals; Halogenated Hydrocarbons; Halothane; Hippocampus (Brain); Inhalant dose form; Inhibitory Synapse; Interneurons; Intoxication; Ionophores; Isoflurane; Laboratories; Lead; Link; Literature; Measures; Mediating; Membrane; Mental Depression; Methods; Modification; Molecular; Motor; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Narcotics; Nerve; Neuraxis; Neurons; Neurotransmitters; Numbers; Outcome; Pathway interactions; Pattern; Perception; Perforant Pathway; Pharmaceutical Preparations; Physiologic pulse; Play; Population; Preparation; Prevention; Principal Investigator; Pulse taking; Pyramidal Cells; Rattus; Recording of previous events; Relative (related person); Research; Research Personnel; Role; Role playing therapy; Ryanodine; Sensory; Site; Slice; Solvents; Structure; Students; Study Section; Synapses; Synaptic Transmission; System; Teenagers; Testing; Thalamic structure; Thinking; Time; Toluene; Trichloroethanes; Trichloroethylene; Work; addiction; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; channel blockers; clinically relevant; experience; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; inhalation drug abuse; inhibitor/antagonist; mossy fiber; neuronal cell body; patch clamp; postsynaptic; presynaptic; programs; receptor; release of sequestered calcium ion into cytoplasm; research study; response; sevoflurane; synaptic function; synaptic inhibition; transmission process; uptake; voltage

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.

吸入溶剂滥用是美国青少年中一个日益严重的问题，并可能导致滥用 其他药物。我们研究的长期目标是更好地了解 探讨这些药物的作用机制，以便为治疗和治疗提供合理的策略。 预防吸入溶剂滥用。有证据表明吸入溶剂对中枢神经有作用 系统（CMS）突触，但谷氨酸和γ-氨基丁酸影响的重要性 (GABA) 突触仍然未知。一些溶剂（例如甲苯）似乎可以增强 GABA- 介导的抑制性传播，而另一些似乎通过改变谷氨酸来破坏 CMS 功能 介导的兴奋。我们实验室的初步结果表明，甲苯可以同时作用于 突触的类型及其综合效应会破坏神经元的正常回路功能。这 拟议的研究将使用大鼠海马脑中已充分表征的 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并诱发 GABA 和谷氨酸受体的组合可以完全阻断反应 对手。具体目标如下： 1) 确定吸入溶剂是否会改变 GABA- 介导的传播。 2) 确定溶剂是否改变谷氨酸介导的突触 回应。 3) 研究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对谷氨酸介导的兴奋性的影响 突触后电位。平行研究将确定溶剂引起的影响的程度 CA 1 神经元放电是通过影响 GABA 受体/CI 通道来实现的。吸入 溶剂可能会产生类似于吸入麻醉剂的效果，我们已经对此进行了研究 在我们实验室工作超过十五年。综合起来，结果将可以进行定量比较 药物对常见滥用溶剂的谷氨酸和 GABA 介导的传输的影响 包括：甲苯、1,1,1-三氯乙烷、三氯乙烯。

项目成果

Abused inhalants enhance GABA-mediated synaptic inhibition.

滥用吸入剂会增强 GABA 介导的突触抑制。

• 发表时间: 2009-09
• 作者: MacIver; M Bruce
• 通讯作者: M Bruce