␣-Synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease. The native protein is a major component of nigral Lewy bodies in Parkinson's disease, and full-length ␣-synuclein accumulates in Lewy neurites. Here we present evidence that ␣-synuclein levels are elevated in midbrain dopamine (DA) neurons of chronic cocaine abusers. Western blot and immunoautoradiographic studies were conducted on postmortem neuropathological

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... pecimens from cocaine users and age-matched drug-free control subjects. The results demonstrated that ␣-synuclein levels in the DA cell groups of the substantia nigra/ventral tegmental complex were elevated threefold in chronic cocaine users compared with normal age-matched subjects. The increased protein levels in chronic cocaine users were accompanied by changes in the expression of ␣-synuclein mRNA in the substantia nigra and ventral tegmental area. Although ␣-synuclein expression is prominent in the hippocampus, there was no increase in protein expression in this brain region. The levels of ␤-synuclein, a possible negative regulator of ␣-synuclein, also were not affected by cocaine exposure. ␣-Synuclein protein levels were increased in the ventral tegmental area, but not the substantia nigra, in victims of excited cocaine delirium who experienced paranoia, marked agitation, and hyperthermia before death. The overexpression of ␣-synuclein may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse. However, the accumulation of ␣-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.