The alpha(2) adrenoceptor antagonist idazoxan alleviates L-DOPA-induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6-hydroxydopamine-lesioned rats.
L-DOPA-induced dyskinesia is characterised by debilitating involuntary movement, which limits quality of life in patients suffering from Parkinson's disease. Here, we investigate effects of the a2 adrenoceptor antagonist idazoxan on L-DOPA-induced dyskinesia as well as on alterations of extracellular L-DOPA and dopamine (DA) levels in the striatum in dyskinetic rats. Male Wistar rats were unilaterally lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA/benserazide to induce stable dyskinetic movements.Administration of idazoxan [(9 mg/kg, intraperitoneal (i.p.)]significantly alleviated L-DOPA-induced dyskinesia, whereas idazoxan (3 mg/kg, i.p.) did not affect dyskinetic behaviour.Bilateral in vivo microdialysis revealed that idazoxan 9 mg/kg reduces extracellular peak L-DOPA levels in the lesioned and intact striatum as well as DA levels in the lesioned striatum. In parallel, the exposure to idazoxan in the striatum was monitored.Furthermore, no idazoxan and L-DOPA drug-drug interaction was found in plasma, brain tissue and CSF. In conclusion, the decrease of L-DOPA-derived extracellular DA levels in the lesioned striatum significantly contributes to the anti-dyskinetic effect of idazoxan.
Buck
Kerstin
K
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Voehringer
Patrizia
P
Ferger
Boris
B
D018663:Adrenergic Agents / Q000633:toxicity; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D019329:Idazoxan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D017551:Microdialysis / Q000379:methods; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000188:drug therapy / Q000209:etiology; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry / Q000379:methods
D018663:Adrenergic Agents; D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D007980:Levodopa; D016627:Oxidopamine; D004298:Dopamine; D019329:Idazoxan