title: The effect of piribedil on L-DOPA-induced dyskinesias in a rat model of Parkinson's disease: differential role of α(2) adrenergic mechanisms.
abstract: Piribedil is a non-ergoline, dopamine D(2)/D(3) receptor agonist with α(2) adrenoceptor antagonist properties that has been used in the treatment of Parkinson's disease (PD). Noradrenergic neurotransmission may be involved in the pathogenesis of dyskinesias induced by chronic treatment with L-DOPA (3,4-dihydroxyphenylalanine, levodopa), but its role in the in vivo action of piribedil or on different subclasses of abnormal involuntary movements (AIMs) remains unclear. The aims of this study were therefore (1) to investigate the anti-dyskinetic effects of piribedil on L-DOPA-induced contralateral turning behaviour, locomotive dyskinesias (LD), axial dystonia (AD), orolingual dyskinesia (OD) and forelimb dyskinesia (FD) and (2) to compare these effects to the α(2) adrenoceptor antagonist, idazoxan, or the α(2) adrenoceptor agonist, clonidine. Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and injected intraperitoneally twice daily with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg). After 3 weeks, the effects of piribedil (5, 15, 40 mg/kg), clonidine (0.15 mg/kg), idazoxan (10 mg/kg) and combinations of these drugs were scored during 2 h. Pre-treatment with 5 and 40 mg/kg, but not 15 mg/kg, of piribedil reduced turning behaviour and AD, OD and FD, but piribedil increased LD at the 40 mg/kg doses compared to the L-DOPA group. Idazoxan induced similar effects as piribedil (40 mg/kg), except that it had no effect on LD. Idazoxan blocked the effect of piribedil on AD and FD. Clonidine reduced all AIMs except OD, possibly because of its sedative effect. Clonidine blocked the effect of piribedil on AD, OD and FD. These data suggest a differential involvement of α(2) adrenergic receptors in the action of piribedil on different subclasses of L-DOPA-induced dyskinesias.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany. manfred.gerlach@uni-wuerzburg.de
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
authors.forename: Paul
authors.initials: P
authors.lastname: Halley
authors.forename: Peter
authors.initials: P
authors.lastname: Riederer
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Buuse
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001545:Benserazide / Q000008:administration & dosage; D003000:Clonidine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000517:prevention & control*; D004421:Dystonia / Q000139:chemically induced / Q000188:drug therapy; D005146:Facial Asymmetry / Q000139:chemically induced / Q000188:drug therapy; D019329:Idazoxan / Q000008:administration & dosage; D007980:Levodopa / Q000009:adverse effects*; D008124:Locomotion / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D010891:Piribedil / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D018709:Statistics, Nonparametric; D034941:Upper Extremity / Q000503:physiopathology
chemical_list: D018663:Adrenergic Agents; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000978:Antiparkinson Agents; D018341:Receptors, Adrenergic, alpha-2; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D010891:Piribedil; D003000:Clonidine; D019329:Idazoxan