To simulate low levels of exposure to a complex I inhibitor during a normal life span, SpragueDawley and Lewis rats were systemically and chronically exposed to low levels of rotenone via an intrajuglar cannula attached to a subcutaneous osmotic minipump (55). Lewis rats developed more consistent lesions and were therefore used exclusively for further studies. At first the doses of rotenone used ranged from 1 to 12 mg/kg/day. At high doses rotenone produced systemic cardiovascular toxicity and nonspecific brain lesions similar to that observed by others (56,57). Downward titration of rotenone dosing resulted in less systemic toxicity and more specific nigrostriatal dopaminergic degeneration. The optimal dose for inducing PD-like pathology was determined to be 2-3 mg/kg/day. It is important to note at this point that even at the "optimal dose," only 30% to 50% of Lewis rats demonstrated PD-like pathology. Nonetheless, systemic, low levels of rotenone administration reproduced pathologic features characteristic of PD (55). Intrajugular cannulation surgeries are however labor-intensive and increases the risk of postsur-gical complications. Therefore, an alternative route was developed to administer rote-none. Instead of cannulation and vascular administration rotenone was administered by subcutaneously placed osmotic minipumps that released rotenone into the body cavity (55,58). Subcutaneous administration of rotenone, at 2-3 mg/kg/day in Lewis rats, also produced selective nigrostriatal dopaminergic lesions as previously reported (55). Rotenone, emulsified in sunflower oil, and administered daily by intraperitoneal injections was also able to induce parkinsonian symptoms and degeneration of nigral dopaminergic neurons in Sprague-Dawley rats (59).
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