Abused Inhalant Actions at GABA and Glutamate Synapses

GABA 和谷氨酸突触的滥用吸入行为

基本信息

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
项目类别：
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

项目摘要

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，以便为治疗提供合理的策略和预防吸入溶剂滥用。有证据表明中枢神经上吸入溶剂作用系统（CMS）突触，但在谷氨酸和γ-氨基丁酸上效应的重要性（GABA）突触仍然未知。一些溶剂（例如甲苯）似乎增强了GABA- 通过改变谷氨酸 - 介导的激发。我们实验室的初步结果表明，甲苯可以在两者中起作用突触的类型和结合效应的类型是神经元的正常电路功能。这拟议的研究将使用大鼠海马大脑中特征良好的CA 1神经元回路切片。 CA 1电路使用GABA和谷氨酸进行快速的单突触传播并诱发 GABA和谷氨酸受体的组合可以完全阻止反应对手。具体目的如下：1）确定吸入的溶剂是否改变了GABA- 介导的传输。 2）确定溶剂是否改变了谷氨酸介导的突触回答。 3）研究氨基酸溶剂作用的细胞和分子机制突触。电生理记录将与选择性NMDA和AMPA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潜力。平行研究将确定溶剂诱导的作用的程度在CA 1上，神经元排出通过对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，我们已经研究了TOR 在我们的实验室中有十五年。综上所述，结果将允许定量比较药物对常见滥用溶剂的谷氨酸和GABA介导的传播的影响包括：甲苯，1,1,1-三氯乙烯和三氯乙烯。