Neurochemical Responses to Lesions of Dopaminergic Neurons: Implications for Compensation and Neuropathology

Abstract

Parkinson's disease is associated with a relatively selective loss of dopamine (DA) neurons of the nigrostriatal projection. A considerable amount of information regarding Parkinson's disease has come from animal studies using the selective neurotoxin 6-hydroxydopamine (6-OHDA). This compound is selectively accumulated in catecholamine neurons, where it autoxidizes to form such toxic species as superoxide anions, hydrogen peroxide, hydroxyl radicals, and 6-OHDA quinones. 6-OHDA-lesioned rats, like patients with Parkinson's disease, show a “preclinical phase” until the loss of striatal DA exceeds 80-90%. The absence of gross neurological dysfunction despite extensive loss of DA neurons is associated with an increase in the capacity of the remaining DA neurons to deliver transmitter to denervated sites. Studies have suggested that this apparent increase in DA efflux per terminal is because of a reduction in DA reuptake as well as an increase in DA release from residual terminals. The underlying mechanism for the loss of DA neurons in Parkinson's disease is unknown. The binding of DA to cysteinyl residues may serve as an index of DA oxidation; it also may be a cytotoxic event. These events appear to be sufficient for a small number of DA terminals to maintain much of the control over striatal events that normally is exerted by the full complement of nigrostriatal neurons. On the other hand, like 6-OHDA, DA itself can oxidize and exert a selective, toxic effect on DA neurons. Thus, it is possible that the increase in the turnover of DA within remaining neurons contributes to the progressive neurodegenerative process while also reducing the symptoms of DA neuron loss.