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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.

吸入溶剂滥用在美国青少年中是一个日益严重的问题，并可能导致滥用