Objectives: 

Paraoxon (POX) is a highly neurotoxic organophosphate insecticide that acts by inhibition of the enzyme acetylcholinesterase, resulting in cholinergic toxicity. However, it also has a direct and immediate effect on the dopaminergic system, as we have shown in previous work. In the present study we have studied the involvement of NMDA receptors and nitric oxide (NO) on striatal dopamine (DA) release induced by POX in conscious and freely-moving rats.

Materials: 

POX, NMDA receptor antagonists AP5 and MK-801, and nitric oxide synthase (NOS) inhibitor L-NAME, have been administrated directly in striatum of female Sprague-Dawley adult rats (250-300 g, 4-6/group) through a microdialysis probe. DA levels, sampled by microdialysis, have been measured by High-Performance Liquid Chromatography with Electrochemical Detection (HPLC-EC). The statistical analysis was made by ANOVA/Student-Newman-Keuls test. Significant differences: P< 0,05 and P< 0,01.

Results: 

Intrastriatal administration of 5 mM POX increased striatal DA to 1017 ± 181%, with respect to basal levels. Infusion of 5 mM POX in 650 mM AP5 pre-treated animals, increased striatal DA levels to 543 ± 80%, with respect to basal levels, this increase being 47% smaller than that induced by POX in non-pretreated animals. In the same way, infusion of 5 mM POX in 100 mM L-NAME pre-treated animals reduced 60,2% the increase produced by POX as compared to non-pre-treated rats. Nevertheless, the pre-treatment with MK-801 (500 mM) did not produce any effect on POX-induced dopamine release.

Conclusions: 

These results suggest that POX appears to act, at least in part, through an overstimulation of NMDA receptors with NO production to induce DA release, since the administration of NMDA antagonist AP5 and NOS inhibitor L-NAME partially blocked the POX-induced DA release from rat striatum. The absence of MK-801 effect suggests that POX could binds in a competitive way to the NMDA receptors.