Behavioral and neurochemical effects of noradrenergic depletions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine in 6-hydroxydopamine-induced rat model of Parkinson's disease.
In Parkinson's disease, besides the dopaminergic neurodegeneration, locus coeruleus noradrenergic neurons degenerate as well. Noradrenergic neurons have potential anti-parkinsonian, neuromodulatory and neuroprotective properties. Presently, an animal model with dopaminergic lesion has been used as a standard model of Parkinson's disease. The behavioral effects of dopaminergic agents in a Parkinson's animal model with additional noradrenergic lesions has not been studied so far. Here, the behavioral effects of dopaminergic agents L-DOPA (15 mg/kg) and D-amphetamine (4 mg/kg) in two different pathophysiological conditions have been explored; One group involving only dopaminergic deficiency with 6-hydroxydopamine (6-OHDA) and the other group with both dopaminergic and noradrenergic deficiency with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). DSP-4 specifically depleted noradrenaline from locus coeruleus terminal fields. 6-OHDA lesion depleted dopamine and its metabolites DOPAC, HVA and 3-MT in the regions of basal ganglia and it was potentiated by additional locus coeruleus denervation. Dopaminergic lesion produced catalepsy and hypoactivity. Hypoactivity in openfield was potentiated by additional noradrenergic denervation of locus coeruleus neurons. L-DOPA produced effective anticataleptic activity in group with both dopaminergic and noradrenergic lesions and D-amphetamine was found to be more effective in group only with dopaminergic lesions, indicating increased dopaminergic neurodegeneration after noradrenergic lesions. L-DOPA produced hyperactivity in dual neurodegenerated group indicating its differential activity in an animal model with noradrenergic and dopaminergic lesions. These findings indicate the neuroprotective and symptomatic role of noradrenergic neurons. It implicates the importance of noradrenergic pathophysiology in Parkinson's disease and its treatment and need for a more relevant animal model.
Srinivasan
J
J
Zoological institute, Neuropharmacology, University of Tuebingen, Auf der Morgenstelle 28E, 72076 Tuebingen, Germany.
Schmidt
Werner J
WJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018663:Adrenergic Agents / Q000633:toxicity*; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines / Q000633:toxicity*; D001923:Brain Chemistry / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency; D015259:Dopamine Agents / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000172:deficiency*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018663:Adrenergic Agents; D001596:Benzylamines; D015259:Dopamine Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D014443:Tyrosine; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; C012102:DSP 4; C008404:3-methoxytyrosine; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid