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 [3H]dopamine ([3H]DA) release were measured in the striatum. The functional studies showed that paraquat exposure attenuated dopamine (DA) release evoked by α3/α6β2* (nAChR that is composed of the α3 or α6 subunits, and β2; 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 α4β2* (nAChR containing α4 and β2 subunits, but not α3 or α6) nAChRs, present on both DA terminals and striatal neurons. Paraquat treatment decreased α4β2* but not α3/α6β2* nAChR expression. The differential effects of paraquat on nAChR expression and receptor-evoked [3H]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.
Footnotes
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This work was supported by National Institutes of Health Grants NS42091 and NS47162 (to M.Q.), MH53631 and DA12242 (to J.M.M.), and ES012077 (to D.A.D.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.141861.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; α3/α6β2*, nAChR that is composed of the α3 or α6 subunits, and β2; α4β2*, nAChR containing α4 and β2 subunits, but not α3 or α6; DA, dopamine; [3H]DA, [3H]dopamine; BSA, bovine serum albumin; ANOVA, analysis of variance.
- Received June 5, 2008.
- Accepted July 3, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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