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.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000838:Anions; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000494:pharmacology*; D004734:Energy Metabolism; D005260:Female; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000838:Anions; D002712:Chlorides; D005971:Glutamates; D009942:Organometallic Compounds; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C010360:triethyllead; D000255:Adenosine Triphosphate; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase