Distribution of Exposed Organic Solvent in the Brain and its Effect on GABA_A Receptor

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1. Establishment of a new system for exposing organic solvents to small animalsA system suitable for exposing m-xylene to rats was made, and a series of experiments was conducted using this system. The exposure system was easy to handle, and was useful.2. Effects of m-xylene exposure on GABA_A receptor in the brainAutoradiographic study was done using three ligands specific to GABA_A receptors. Autoradiography using [^<35>S]t-butylbicyclophosphorothionate revealed a significant increase in the binding in the cerebellum, whereas that using [^3H]flunitrazepam showed no significant changes. To further investigate the possibility of a receptor subunit-specific effect of m-xylene, autoradiogram using [^3H]Ro15-4513 was obtained. Significant changes in binding were found in the II-IIIth layer of the cerebral cortex, CA1, Inferior colliculus and in the granule cells of the cerebellum. The increase in the binding in the granule cells seemed to be a subunit-specific change, possibly due to alteration in alpha6 subunit-containing receptors.3. Measurement of m-xylene concentration in several areas of the brainThe levels of m-xylene on and after the exposure were measured, and referenced with its metabolite concentration in urine.4. Measurement of m-methylhippuric acid in urine on and after the exposureThe levels of m-methylhippuric acid were measured on and after the exposure. While m-xylene level and m-methylhippuric acid level paralleled during the exposure, the two levels decreased in a different manner after the exposure.These findings taken together, the basic data to develop a new biological effect monitoring of m-xylene were obtained. The new biological monitoring method will use changes in GABA_A receptor as indices of biological effect, and metabolite of m-xylene in urine (m-methylhippuric acid and/or its precursor m-tolualdehyde) as indices of the exposure, respectively.