Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats.
Parkinson's disease is characterized not only by a progressive loss of dopaminergic neurons in the substantia nigra but also by a degeneration of locus coeruleus noradrenergic neurons. The present study addresses the question of whether a partial neurodegeneration of dopaminergic neurons using 6-hydroxydopamine in rat, not sufficient to produce motor disturbances, is potentiated by prior selective denervation of locus coeruleus noradrenergic terminal fields using N-ethyl-2-bromobenzylamine. Two types of denervations, one causing dopamine deficiency alone and the other causing noradrenaline and dopamine deficiency, were performed. Noradrenaline, 5-hydroxytryptamine, 5-hydroxyindole acetic acid, dopamine and its metabolites were analysed in various brain regions. Behaviour was evaluated by catalepsy tests and activity box. N-ethyl-2-bromobenzylamine selectively depleted noradrenaline from neurons of locus coeruleus origin. Decreased dopamine content in the striatum, substantia nigra and pre-frontal cortex was observed after dopaminergic lesion with 6-hydroxydopamine (42.9%). Additional locus coeruleus noradrenaline depletion with N-ethyl-2-bromobenzylamine aggravated the dopamine depletion (61.2%). The lesion in the noradrenergic and dopaminergic neurodegenerated group was not sufficient to induce consistent catalepsy and akinesia. However, after a subthreshold dose of haloperidol (0.1 mg/kg), the expression of catalepsy and akinesia was strong in the dual-lesioned group and less in the 6-hydroxydopamine-lesioned group. These results indicate that denervation of locus coeruleus noradrenergic terminals with N-ethyl-2-bromobenzylamine potentiates the 6-hydroxydopamine-induced partial dopaminergic neurodegeneration and parkinsonian symptoms. Based on the present findings and existing reports, it can be concluded that noradrenergic neurons of locus coeruleus have neuromodulatory and neuroprotective properties on the dopaminergic neurons of basal ganglia and that noradrenergic degeneration may contribute to the aetiology and pathophysiology of Parkinson's disease.
Srinivasan
J
J
Zoological Institute, Neuropharmacology, University of Tuebingen, Auf der Morgenstelle 28E, 72076, Tuebingen, Germany.
Schmidt
W J
WJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal; D001596:Benzylamines / Q000633:toxicity; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D006719:Homovanillic Acid / Q000032:analysis / Q000378:metabolism; D007031:Hypothalamus / Q000737:chemistry / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D008474:Medial Forebrain Bundle / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013378:Substantia Nigra / Q000503:physiopathology*; D013788:Thalamus / Q000737:chemistry / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
D018663:Adrenergic Agents; D001596:Benzylamines; D018492:Dopamine Antagonists; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D014443:Tyrosine; D016627:Oxidopamine; D006220:Haloperidol; C012102:DSP 4; C008404:3-methoxytyrosine; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid