Stimulus-evoked glutamate release is diminished by acute exposure to uranium in vitro.
Uranium is used in civilian applications, in the manufacture of nuclear fuel, and by the military for munitions and armament, but little information is available on its neurotoxicity. Neurological dysfunctions have been observed after chronic exposure in both animals and humans, but the actions of acute exposure on amino acid neurotransmission have not been investigated. The following study was performed to examine the effects of uranyl ion (UO(2)(+2)) on hippocampal glutamatergic and GABAergic function as possible bases for the neurotoxicity and to assess the direct effects on the exocytotic process. Nominal UO(2)(+2) concentrations were applied to superfused hippocampal synaptosomes to permit estimation of the metal's potency on endogenous transmitter release in the presence and absence of Ca(+2). K(+)-evoked glutamate release was diminished in the range of 10 nM-316 microM UO(2)(+2), resulting in an IC(50) of 1.92 microM. In contrast, the potency of UO(2)(+2) to decrease stimulated GABA release was reduced, producing an IC(50) approximately 2.6 mM. In the absence of Ca(+2) in the superfusion medium there was no systematic change in the magnitude of glutamate or GABA release, suggesting that UO(2)(+2) does not possess Ca(+2)-mimetic properties. The inhibitory potency of UO(2)(+2) on glutamate release is similar to the potencies of other multivalent metal ions, suggesting by inference an action exerted on voltage-sensitive Ca(+2) channels. The bases for the reduced potency to inhibit GABA release is not known, but differential sensitivity to other heavy metals has been reported for glutamate and GABA neurotransmission. These findings indicate a profile of neurotoxicity not unlike that of other metal ions, and indicate the importance of extending subsequent studies to chronic exposure models.
Vietti
Kimberly R N
KR
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, P. O. Box 1649, Peoria, IL 61656, USA.
Lasley
Stephen M
SM
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014501:Uranium / Q000378:metabolism / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018698:Glutamic Acid; D014501:Uranium; D005680:gamma-Aminobutyric Acid; D011188:Potassium; D002118:Calcium