Mechanisms of action of paraoxon, an organophosphorus pesticide, on in vivo dopamine release in conscious and freely moving rats.

Paraoxon is the active metabolite of parathion, an organophosphorus pesticide which can cause neurotoxic effects in animals and humans. In the present work, we investigated the effects of 5 mM paraoxon on striatal dopamine, DOPAC and HVA levels in conscious and freely moving rats, after treatment with TTX, reserpine, nomifensine, KCl, Ca-free/EDTA medium, AP-5 or L-NAME. The intrastriatal administration of paraoxon for 60 min, through the microdialysis probe, significantly produced an increase of the dopamine to 1066 ± 120%, relative to basal levels. Administration of paraoxon to 20 μM TTX, 10 mg/kg reserpine or Ca-free/EDTA medium-pretreated animals decreased the dopamine levels to 73%, 81%, and 70%, respectively, when compared with the effect of 5 mM paraoxon. Infusion of 50 μM nomifensine induced a maximal increase in extracellular dopamine levels to 1435 ± 387%, and when nomifensine was coadministered with paraoxon, striatal dopamine levels increased to 2429 ± 417%, an increase that was ∼230% higher that observed with the administration of the pesticide alone. Coinfusion of KCl and paraoxon produced an increase in extracellular dopamine to 1957 ± 445%, that was significantly higher than that observed with POX or KCl (1104 ± 220%) administered individually. Pretreatment with 650 μM AP-5 or 100 L-NAME reduced the effect of paraoxon on extracellular dopamine levels by 49.1% and 53.7%, respectively. Our results suggest that paraoxon induces dopamine release by a vesicular-, Ca-, and deporalization-dependent mechanism, being independent of dopamine transporter. In addition, the paraoxon-induced dopamine release is mediated by glutamatergic and nitrergic neurotransmitter systems.