Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine

Various doses of the neurotoxin 6-hydroxydopamine (6-OHDA) were infused into the substantia nigra-ventromedial tegmental area, caudateputamen nucleus, and red nucleus. A maximum of four successively occurring zones of neuropathology could by detected at all injection sites: (1) A zone of complete absence of neural, glial, and vascular elements due to tissue displacement by the cannula, (2) an area of glial cells, developing over time, which surrounded the cannula tract, (3) a region exhibiting virtually complete loss of neuronal elements, and (4) a zone of selective neuropathological reaction or cellular loss in which some neurons were affected and others were not. All investigators who have histochemically and/or histologically evaluated the effects of intracerebrally administered 6-OHDA agree on the existence and genesis, some non-selective process, of the first three zones. Although some scientists maintain that the fourth zone is where 6-OHDA operates selectively, data are presented in this report that other, well-established processes can account for neuropathology beyond zone 3. Prominent among these are retrograde and anterograde degeneration, ischemia as a function of interruption of blood supply, and nonselective traumatization. In addition, the topography of the injected site (e.g., morphology of affected neurons, degree of myelination) was found to be as important a determinant of the locus of tissue damage as the presumed selectivity of 6-OHDA's action. Furthermore, monoamine oxidase inhibition by nialamide did not appear to increase the neurotoxicity of 6-OHDA. Similarly, 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane was not a more potent cytotoxin than 6-OHDA even though this new neurotoxin has a propane side chain which renders it immune to monoamine oxidase. These observations, taken together, suggest that considerable cautioon should be exercised in interpreting data from experiments in which 6-OHDA, or related neurotoxins, are used to uncover catecholaminergic mechanisms of behavior and other functional processes.