Effect of disulfiram administration on glutamate uptake by synaptosomes in the rat brain.
Although disulfiram used as a pharmacological agent in the treatment of alcoholism is reported to act on both peripheral and central nervous systems with several adverse effects, the neurotoxic property of the drug has not been properly elucidated. We observed that the chronic administration of the drug to rats significantly inhibited synaptosomal (Na+,K+)-ATPase and basal Mg(2+)-ATPase activities. Further, the uptake of gamma-aminobutyric acid and L-glutamate which rely on the energy provided by this system was depleted following chronic drug administration. Similar findings were observed when the isolated synaptosomes were treated with the drug in an in vitro system. Further, treatment of synaptosomes with ouabain, a known inhibitor of (Na+, K+)-ATPase resulted in significant depletion of 3H-GABA and L-[3H]glutamate uptake into synaptosomes indicating the importance of the enzyme in the uptake mechanism. However, diethyldithiocarbamate, a major metabolite of disulfiram did not elicit any change in either the enzyme activity or the uptake of these neurotransmitters. On the basis of these evidences, we suggest that the chronic disulfiram administration attenuated the neurotransmitter uptake mechanism and resulted in higher extracellular concentration of glutamate that could lead to glutamate-induced neurotoxicity.
Mamatha
R K
RK
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India.
Nagendra
S N
SN
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004221:Disulfiram / Q000633:toxicity*; D004050:Ditiocarb; D004334:Drug Administration Schedule; D018698:Glutamic Acid / Q000502:physiology*; D007700:Kinetics; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D014179:Neurotransmitter Uptake Inhibitors; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004050:Ditiocarb; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D004221:Disulfiram