The effect of the alpha2-adrenoreceptor antagonist idazoxan against 6-hydroxydopamine-induced Parkinsonism in rats: multiple facets of action?
The alpha2-adrenoreceptor antagonist idazoxan counteracts catalepsy induced by neuroleptic agents and improves Parkinsonian signs in 1-methyl-4-phenyl 1,2,3,6,tetrahydropyridine-treated monkeys and in patients. The present study addressed the question of whether systemic administration of idazoxan (1.5 mg/kg i.p.) improves Parkinsonian symptoms in a rat model of permanent dopaminergic neurodegeneration. Dopaminergic degeneration was induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). Parkinsonian behaviour was assessed by catalepsy and open-field exploratory behaviour tests. Since dopaminergic and serotonergic mechanisms are thought to account for the anti-cataleptic/anti-Parkinsonian property of idazoxan, dopamine, 5-hydroxytryptamine (5-HT) and its metabolites in the regions of the basal ganglia and prefrontal cortex were analysed by HPLC. 6-OHDA lesions in the MFB produced catalepsy and hypoactivity in the open field and depleted dopamine and its metabolites in the basal ganglia and prefrontal cortex, but did not affect 5-HT. Treatment with idazoxan counteracted the observed Parkinsonian behaviour in 6-OHDA-lesioned rats and increased the spontaneous open-field activity in control rats. In both 6-OHDA and control animals, idazoxan increased DA level in the prefrontal cortex, but not in any other structures including the striatum. Idazoxan also increased the levels of 5-HT in the anterior striatum, prefrontal cortex and the ventral tegmental area of both 6-OHDA and control animals. These findings indicate that systemic administration of idazoxan counteracts 6-OHDA-induced Parkinsonian symptoms in rats and that both dopaminergic and serotonergic mechanisms could contribute to its anti-Parkinsonian effect.
Srinivasan
J
J
Zoological Institute, Neuropharmacology, University of Tübingen, Auf der Morgenstelle 28E, 72076 Tübingen, Germany.
Schmidt
Werner J
WJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002375:Catalepsy / Q000188:drug therapy; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000517:prevention & control*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D016627:Oxidopamine; D004298:Dopamine; D019329:Idazoxan