Abused Inhalant Actions at GABA and Glutamate Synapses

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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.