EFFECTS OF KAINIC ACID ON ION DISTRIBUTION AND ATP LEVELS OF STRIATAL SLICES INCUBATED IN VITRO |
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Authors: | K. Biziere J. T. Coyle |
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Affiliation: | Departments of Pharmacology and Experimental Therapeutics and Psychiatry and the Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. |
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Abstract: | Abstract— To determine the mechanism of neurotoxicity of kainic acid, striatal slices (350μ) were incubated in oxygenated Krebs buffer with kainic acid and other depolarizing agents; and the alterations in the uptake and retention of 22Na+, 86Rb+ (as a measure of K +), 3HzO and the levels of ATP were determined. The excitatory amino acid, L-glutamate (10 mM) increases striatal slice uptake and retention of Na+, K+ and H2O but decreases ATP levels whereas the neuroexcitant, A'-methyl aspartate, increases only Na+ and H2O. Veratridine (100μM), which opens electrogenic sodium channels, and ouabain (100μM), which inhibits Na+-K+ ATPase, both elevate striatal Na+ and H2O but considerably reduce K+ and ATP. The effects of these different depolarizing agents on the parameters examined are consistent with their mechanisms of actions and support the validity of this in vitro method. Although 10mM-kainate significantly depresses striatal K+ and ATP, lower concentrations of kainate (5mM-0.1μ) elevate striatal uptake of Na+ but do not markedly affect H2O, K+ or ATP. Kainate (10mM-lμM) does not exhibit additivity with 10 mM-glutamate with respect to Na+ permeability but does significantly potentiate glutamate's ATP depleting effects. Injection of 10 nmol of kainate into the striatum in vivo causes a reduction in striatal ATP 1 h afterward which is comparable to that occurring in vitro with 10mM-kainate alone or with lower concentrations of kainate (≥1/μM) with 10 mM-glutamate. These results suggest that kainate alone is directly neurotoxic at 10mM or neurotoxic at lower concentrations in combination with the high intrasynaptic levels of glutamate on neurons receiving glutamatergic innervation. |
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