Selective inhibition of synaptosomal gamma-aminobutyric acid uptake by triethyllead: role of energy transduction and chloride ion.
Triethyllead (TEL) is a CNS neurotoxin producing bizarre neurobehavioral changes. The principal objective of this study was to determine if TEL-induced defects in energy metabolism were responsible for the inhibition of synaptosomal Na+-dependent high-affinity uptake of gamma-aminobutyric acid (GABA). A dose-dependent inhibition of GABA uptake (ID50 = 10 microM TEL) was found during 30-s incubations. Uptake of glutamate was more resistant to the inhibitory effects of TEL. A TEL-induced Cl(-)-dependent synaptosomal deficit of ATP was observed. Such deficit in high-energy phosphate was time-dependent and did not occur in the absence of Cl- or as early as 30 s. Inhibition of GABA uptake, on the other hand, was a Cl(-)-independent phenomenon and was observed at as early as 30 s. TEL was not competitive with Na+ or GABA itself, as the effects of TEL were not overcome with high [Na+] or [GABA]. These results indicate that the locus of TEL inhibition of GABA uptake is not a Cl(-)-dependent event and does not involve a perturbed transmembrane electrochemical gradient, due to either an observed mitochondrial defect or an inhibition of Na+, K+-ATPase directly.