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 intraneuronal inclusions containing cytoskeletal proteins such as neurofilaments 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 the primary pathology in Parkinson's disease is localized to the dopaminergic system, we set out to determine if perturbations in cholinergic systems are a consequence of dopaminergic neuron loss. Therefore, following intracerebral microinjections of 6-hydroxydopamine in rats, the activity of cholinergic neurons was measured by hemicholinium binding in cholinergic terminal fields and perturbations in cytoskeletal proteins were examined in dopaminoceptive neurons using immunocytochemistry. The 6-hydroxydopamine injections robustly reduced the number of monoaminergic cell bodies in the lateral midbrain and dramatically decreased dopamine and its major metabolites in dopaminergic projection sites. This treatment increased hemicholinium binding in the prefrontal cortex (200%) and amygdala (284%); however, despite previous 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 cytoskeletal proteins was observed following either injections of moderate doses of the toxin directly into the medial forebrain bundle or after high doses were administered intracerebroventricularly. These results suggest that removal of dopaminergic inputs to the forebrain results in hyperactivity of the cholinergic systems but is not sufficient to induce postsynaptic perturbations in cytoskeletal proteins which occur in neurodegenerative diseases.
Muma
N A
NA
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
Lee
J M
JM
Gorman
L
L
Heidenreich
B A
BA
Mitrovic
I
I
Napier
T C
TC
D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D018678:Cholinergic Agents / Q000493:pharmacokinetics; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D006426:Hemicholinium 3 / Q000493:pharmacokinetics; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009928:Organ Specificity; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D018678:Cholinergic Agents; D003598:Cytoskeletal Proteins; D011954:Receptors, Dopamine; D006426:Hemicholinium 3; D016627:Oxidopamine; D004298:Dopamine