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

Introduction: Paraoxon is the neurotoxic metabolite of organophosphorus (OP) insecticide parathion and causes acute toxicity by inhibition of acetylcholinesterase (AChE). AChE inhibition leads to the accumulation of acetylcholine in cholinergic synapses and hence results in an overstimulation of the cholinergic system. Reports on changes in the level of γamino butyric acid (GABA) during OP-induced convulsion have been controversial. In the present study we used cortical and hippocampal synaptosomes from rats after paraoxon poisoning to study the alterations of GABA uptake. Methods: Male Wistar rats (200-270 g) were used in this study. Animals were given a single intraperitoneal injection of corn oil (control group) or paraoxon (0.1, 0.3, or 0.7 mg/kg). [H] GABA uptake by cortical and hippocampal synaptosomes was measured 30 min, 4 h, and 18 h after exposure (n = 7 rats/group). Type of transporter involved in the uptake was also determined by using β-alnine and L-diaminobutyric acid (L-DABA), which are glial and neuronal GABA uptake inhibitors, respectively. Results: GABA uptake was significantly (p<0.001) reduced by both cortical (18-32%) and hippocampal (16-21%) synaptosomes compared with their respective control groups at all 3 time points after administration of the convulsive dose (0.7 mg/kg) of paraoxon. β-alnine had no inhibitory effect on the uptake, whereas L-DABA abolished most of the transporter mediated GABA uptake. Conclusion: Our results showed that GABA uptake did not change in groups treated with 2 lower doses of paraoxon, which may indicate that the decrease of GABA uptake is convulsion-related. The decrease in GABA uptake, which is probably 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 carried out by a neuronal GABA transporter (GAT), GAT-1.