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NEUROPHARMACOLOGY

Paraquat Exposure Reduces Nicotinic Receptor-Evoked Dopamine Release in Monkey Striatum

The Parkinson's Institute, Sunnyvale, California (K.T.O., N.P., L.C.J., D.A.D., M.Q.); and Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.)

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 3/6β2^* (nAChR that is composed of the 3 or 6 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 4β2^* (nAChR containing 4 and β2 subunits, but not 3 or 6) nAChRs, present on both DA terminals and striatal neurons. Paraquat treatment decreased 4β2^* but not 3/6β2^* 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.

Address correspondence to: Dr. Maryka Quik, The Parkinson's Institute, 675 Almanor Ave., Sunnyvale, CA 94085-2934. E-mail address: mquik{at}parkinsonsinstitute.org