[Mechanism of paraoxon Effect on [[3]H] GABA uptake inhibition in brain synaptosomes of rat]

ABSTRACT

Parathion is an organophosphate compound that is frequently used as an insecticide. Paraoxon is the metabolic product of parathion which previously reported that inhibits GABA uptake by rat cerebral cortex synaptosomes. The aim of this study is to investigate possible underlying inhibitory mechanism[s] of paraoxon on GABA uptake, in synaptosomes prepared from rat cerebral cortex. After preparation of synaptosomes, kinetic studies were performed to determine the effect of paraoxon on K[m] and V[max] of GABA uptake. Acetylcholine and its antagonists [atropine and mecamylamine] were used to evaluate cholinergic dependency of GABA uptake. Type of GABA transporter involved was determined using beta-alanine and DAB A. The results of the study showed that paraoxon significantly decreased V[max] [175.2 +/- 4.23 vs. 80.4 +/- 2.03 pmol/mg protein/min, P<0.001] of GABA uptake while had no effect on its k[m] [9.80 +/- 1.02 vs. 9.09 +/- 0.92micro M in paraoxon and control groups respectively]. DABA significantly decreased GABA uptake [P<0.001] while beta-alanine had no effect. Acetylcholine had no effect on GABA uptake. On the other hand, neither atropine nor mecamylamine could reverse the inhibitory effect of paraoxon on GABA uptake. In conclusion, it seems that paraoxon acts as non-competitive anatagonist of GABA uptake, which affects kinetics of GABA uptake in nerve endings. We also conclude that the inhibitory effect of paraoxon on GABA uptake is cholinergic-independent