Effect of paraoxon on the synaptosomal GABA uptake in rat hippocampus and cerebral cortex

Introduction: Paraoxon (the neurotoxic metabolite of organophosphorus (OP) insecticide, parathion) exerts acute toxicity by inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine in cholinergic synapses and hence overstimulation of the cholinergic system. Since, reports on changes in the level of γ- amino butyric acid (GABA) during OP-induced convulsion have been controversial, in present study we used cortical and hippocampal synaptosomes from rats after paraoxon poisoning to detect changes in GABA uptake. Methods: Male Wistar rats (200-270 g) were used in this study. Animals were given a single intraperitoneal injection of corn oil (vehicle group) or one of doses of paraoxon (0.1, 0.3, or 0.7 mg/kg) and [3H]GABA uptake by cerebral cortex and hippocampal synaptosomes was measured at 30 min, 4 h, and 18 h after the exposure (n= 7 rats/group). Type of transporter involved in the uptake was also determined using β-alnine, and L-diaminobutyric acid (L-DABA), a glial and a neuronal GABA uptake inhibitor, respectively. Results: GABA uptake was significantly (p<0.001) reduced by both cerebral cortex (18-32%) and hippocampal (16-21%) synaptosomes compared with their respective control groups at all three time points after administering 0.7 of paraoxon (convulsive dose). β-alnine had no inhibitory effect on the uptake, whereas L-DABA abolished most of the transporter mediated GABA uptake. Conclusion: Since GABA uptake did not change in other two paraoxon treated groups, it may be indicating that decrement of GABA uptake is convulsion-related. The decrease in GABA uptake, presumably due to a change in the function of GABA transporters, may represent a compensatory response modulating neuronal overexcitation. Most of synaptosomal GABA uptake was blocked by L-DABA, indicating that the uptake was primarily by a neuronal GABA transporter (GAT), GAT-1.