Evidence that punctate intracerebral administration of 6-hydroxydopamine fails to produce selective neuronal degeneration

It is concluded that specificity of neuron destruction can be achieved with 6-OHDA only to the extent that the drug is injected into brain regions which are neurochemically homogeneous.

Abstract

Various doses of 6-hydroxydopamine (6-OHDA) and copper sulfate were injected into brain regions having a different composition of monoamine-containing neurons: The red nucleus, substantia nigra-ventral tegmental area, caudate-putamen nucleus, and thalamus. Brains were subsequently histochemically processed for acetylcholinesterase and NADH-diaphorase activities and for cupric ion; traditional histology was also performed. A maximum of four regions of neuropathology was observed occurring successively in relation to the cannula: (1) A zone of complete absence of neural, glial, and vascular elements due to tissue displacement by the cannula, (2) an area consisting of a dense layer of glia cells 0.05–0.2 mm thick immediately surrounding the cannula tract, (3) a region exhibiting virtually complete loss of neural elements accompanied over time by extensive gliosis, and (4) a zone of neuronal loss probably occurring as a function of retrograde degeneration and/or reaction to other injury processes. Intracerebral insertion of the cannula without fluid infusion or injections of the respective vehicles of CuSO4 and 6-OHDA produced Zone 1 and 2 degeneration at all sites tested; Zone 4 damage was also seen but reliably only in the red nucleus and substantia nigra. Injection of solutions of 6-OHDA and CuSO4 produced Zone 1, 2, and 3 degeneration at all target areas tested. Zone 3 damage was the most prominent neuropathology, and Zone 4 cell loss was observed only in relation to the special anatomical characteristics of the neurons in the brain region infused. It was found that the degree of myelination of a particular brain region markedly influenced the nature and extent of Zone 3 damage. Extensive neuronal degeneration was seen after intrarubral administration of 6-OHDA even though the cell bodies of the red nucleus contain neither dopamine nor noradrenaline. The rigidity and hypokinesia produced by bilateral 6-OHDA injection into the substantia nigra-ventral tegmental area were very similar to the motor manifestations produced by CuSO4. No dose of 6-OHDA was found which both (1) produced neuronal degeneration attributable unequivocally to the action of the drug and (2) affected only those neurons having a particular type of neurotransmitter. We conclude that specificity of neuron destruction can be achieved with 6-OHDA only to the extent that the drug is injected into brain regions which are neurochemically homogeneous. The discrepancies between the interpretation of other investigators and our own results concerning the neurotoxic specificity of 6-OHDA can be resolved by considering the basic morphological characteristics of the neurons affected (e.g., Golgi Type I or II), the topography of the neural region injected (e.g., heavily myelinated or not), and more traditional processes such as retrograde and anterograde degeneration and classical injury reactions.