6-hydroxydopamine-induced lesions of dopaminergic neurons alter the function of postsynaptic cholinergic neurons without changing cytoskeletal proteins

The neuropathological hallmarks of many neurodegenerative diseases are intr aneuronal inclusions containing cytoskeletal proteins such as neurofilament s in Lewy bodies in Parkinson's disease and tau in neurofibrillary tangles in Alzheimer's disease. Dysfunction in dopaminergic and cholinergic systems also exist in both Alzheimer's disease and Parkinson's disease. Because th e primary pathology in Parkinson's disease is localized to the dopaminergic system, we set out to determine if perturbations in cholinergic systems ar e a consequence of dopaminergic neuron loss. Therefore, following intracere bral microinjections of 6-hydroxydopamine in rats, the activity of choliner gic neurons was measured by hemicholinium binding in cholinergic terminal f ields and perturbations in cytoskeletal proteins were examined in dopaminoc eptive neurons using immunocytochemistry. The 6-hydroxydopamine injections robustly reduced the number of monoaminergic cell bodies in the lateral mid brain and dramatically decreased dopamine and its major metabolites in dopa minergic projection sites. This treatment increased hemicholinium binding i n the prefrontal cortex (200%) and amygdala (284%); however, despite previo us reports to the contrary, there were no increases in immunoreactivity for phosphorylated neurofilaments, microtubule-associated protein (MAP) 2, tau or paired helical filament (PHF) tau. This lack of an increase in cytoskel etal proteins was observed following either injections of moderate doses of the toxin directly into the medial forebrain bundle or after high doses we re administered intracerebroventricularly. These results suggest that remov al of dopaminergic inputs to the forebrain results in hyperactivity of the cholinergic systems but is not sufficient to induce postsynaptic perturbati ons in cytoskeletal proteins which occur in neurodegenerative diseases. (C) 2001 Academic Press.