Paraquat exposure reduces nicotinic receptor-evoked dopamine release in monkey striatum

Abstract

Paraquat, an herbicide widely used in the agricultural industry, has been associated with lung, liver, and kidney toxicity in humans. In addition, it is linked to an increased risk of Parkinson's disease. For this reason, we had previously investigated the effects of paraquat in mice and showed that it influenced striatal nicotinic receptor (nAChR) expression but not nAChR-mediated dopaminergic function. Because nonhuman primates are evolutionarily closer to humans and may better model the effects of pesticide exposure in man, we examined the effects of paraquat on striatal nAChR function and expression in monkeys. Monkeys were administered saline or paraquat once weekly for 6 weeks, after which nAChR levels and receptor-evoked [(3)H]dopamine ([(3)H]DA) release were measured in the striatum. The functional studies showed that paraquat exposure attenuated dopamine (DA) release evoked by alpha3/alpha6beta2(*) (nAChR that is composed of the alpha3 or alpha6 subunits, and beta2; the asterisk indicates the possible presence of additional subunits) nAChRs, a subtype present only on striatal dopaminergic terminals, with no decline in release mediated by alpha4beta2(*) (nAChR containing alpha4 and beta2 subunits, but not alpha3 or alpha6) nAChRs, present on both DA terminals and striatal neurons. Paraquat treatment decreased alpha4beta2(*) but not alpha3/alpha6beta2(*) nAChR expression. The differential effects of paraquat on nAChR expression and receptor-evoked [(3)H]DA release emphasize the importance of evaluating changes in functional measures. The finding that paraquat treatment has a negative impact on striatal nAChR-mediated dopaminergic activity in monkeys but not mice indicates the need for determining the effects of pesticides in higher species.

Fig. 1

Paraquat exposure reduced nicotine-evoked α3/α6β2*-mediated ³H-DA release from medial (A) and lateral (B) caudate synaptosomes. Animals were administered 2.5 mg/kg paraquat once weekly for six weeks. The α3/α6β2* nAChR-selective antagonist, α-conotoxinMII, was used to define α3/α6β2* nAChR-evoked ³H-DA release as described in Results. Dose response curves from the paraquat group were significantly different from control, * p < 0.05, ** p < 0.001 (two-way ANOVA). Curves were generated by non-linear regression analysis in GraphPad Prism. All values represent mean ± SEM of 6–8 animals.

Fig. 2

Paraquat exposure did not affect nicotine-evoked α4β2* nAChR-mediated ³H-DA release. Paraquat treatment did not alter α4β2* nAChR-mediated ³H-DA release from either medial (A) or lateral (B) caudate synaptosomes. Animals were administered 2.5 mg/kg paraquat once weekly for six weeks. α4β2* nAChR-mediated release was determined as described in Results. Dose response curves were generated by non-linear regression analysis in GraphPad Prism. All values represent mean ± SEM of 6–8 animals.

Fig. 3

Paraquat exposure did not change α3/α6β2* nAChR expression in the caudate. Paraquat treatment did not significantly alter binding of the α3/α6β2* nAChR-selective ligand ¹²⁵I-α-conotoxinMII in medial (A) or lateral (B) caudate. It also did not affect α-conotoxinMII-sensitive ¹²⁵I-epibatidine binding, an additional measure of α3/α6β2* nAChRs, in medial (C) or lateral (D) caudate. All values represent mean ± SEM of 6–8 animals per group.

Fig. 4

Paraquat treatment reduced α4β2* nAChR expression in the medial and lateral caudate (A. and B. respectively). α4β2* nAChR expression was measured as the level of ¹²⁵I-epibatidine binding remaining in the presence of the α3/α6β2* nAChR-selective antagonist α-conotoxinMII. Significance of difference from control, * p < 0.05 (one-way ANOVA followed by Dunnett’s post hoc test). All values represent mean ± SEM of 6–8 animals per group.