Obesity is a major risk factor associated with a variety of human disorders. While its involvement in disorders such as diabetes, coronary heart disease and cancer have been well characterized, it remains to be determined if obesity has a detrimental effect on the nervous system. To address this issue we determined whether obesity serves as a risk factor for neurotoxicity. Model neurotoxicants, methamphetamine (METH), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and kainic acid (KA), known to cause selective neurodegeneration of anatomically distinct areas of the brain, were evaluated using two models of obesity, leptin-deficient (ob/ob) mice and the diet-induced obesity (DIO) mouse model. Administration of METH or KA resulted in mortality among ob/ob mice but not among their lean littermates. Assessments of multiple indices neurotoxicity provide a consistent portrait: obese mice show enhanced neuronal damage and astrogliosis in comparison to their lean littermates. While METH and MPTP caused striatal dopaminergic nerve terminal degeneration (decreased striatal dopamine and tyrosine hydroxylase protein) and astrogliosis (increase in glial fibrillary acidic protein) in the lean mice, these effects were exacerbated under in ob/ob mice. Similarly, exacerbation of neuronal injury after METH or MPTP was also observed in the DIO model of obesity. Consistent with tbe dopaminergic neurotoxicity seen in obese-mice, KA caused extensive hippocampal neuronal degeneration, as determined by Fluoro-Jade B staining, decreased microtubule-associated protein 2 immunoreactivity and increased GFAP only in the ob/ob mice. The neurotoxic outcome in ob/ob mice remained, exacerbated even when lean and ob/ob mice were dosed with METH or KA based only on a lean body mass. Administration of METH or KA also resulted in the upregulation of the mitochondrial uncoupling protein.2 to a greater extent in the ob/ob mice, an effect known to reduce ATP yield and facilitate oxidative stress and mitochondrial dysfunction. Thus, the obese condition may constitute a potential risk factor for susceptibility to neurotoxicity/neurodegencration.