title: Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.
abstract: Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden. Electronic address: shine@cardiff.ac.uk.
authors.forename: Eunju
authors.initials: E
authors.lastname: Shin
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden.
authors.forename: James T
authors.initials: JT
authors.lastname: Rogers
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria SS 554km 4.500, 09042 Monserrato, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria SS 554km 4.500, 09042 Monserrato, Italy.
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D059331:Adrenergic Neurons / Q000473:pathology*; D000661:Amphetamine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001058:Apomorphine; D001596:Benzylamines / Q000494:pharmacology; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000209:etiology / Q000473:pathology; D005260:Female; D007980:Levodopa / Q000009:adverse effects*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology*; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology; D000076985:Saporins; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D001596:Benzylamines; D054789:Ribosome Inactivating Proteins, Type 1; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D000076985:Saporins; D001058:Apomorphine; C012102:DSP 4
keywords: DBH-Saporin; L-DOPA-induced dyskinesia; Locus coeruleus; Motor impairment; Noradrenaline; Parkinson's disease; Staircase test