Characterization of enhanced behavioral responses to L-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
Long-term treatment of Parkinson's disease with dopamine-replacing agents such as L-3,4-dihydroxyphenylalanine (L-DOPA) is compromised by many side-effects, most notably involuntary movements, L-DOPA-induced dyskinesia. Acute challenge with dopamine-replacing drugs elicits a rotational response in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. This rotation is contraversive to the lesion and is considered to represent an antiparkinsonian effect. More recently, it has become clear that the rotational response shows plasticity and that repeated L-DOPA or apomorphine therapy is accompanied by a marked enhancement in this response. In this study, we demonstrate that the enhanced behavioral response to repeated dopamine-replacement therapy seen in the 6-OHDA-lesioned rat has pharmacological characteristics similar to L-DOPA-induced dyskinesia seen in MPTP-lesioned primates and man. Thus, the magnitude and rate of development of the enhanced response to L-DOPA treatment is related to both the number of doses and the size of the dose of L-DOPA administered. In contrast, de novo administration of dopaminergic drugs that are associated with a lower incidence of dyskinesia, e.g., bromocriptine or lisuride, does not lead to an enhanced behavioral response following repeated treatment. However, following a single "priming" administration of apomorphine, the rotational response elicited by subsequent bromocriptine administrations is enhanced with repeated treatment. Once established, the enhanced behavioral response to repeated L-DOPA-administration (6.5 mg/kg, twice daily) can, like L-DOPA-induced dyskinesia in man and MPTP-treated monkeys, be selectively reduced by coadministration of L-DOPA with the alpha2-adrenergic receptor antagonist yohimbine (10 mg/kg, -95%), the 5-HT uptake inhibitor 5-MDOT (2 mg/kg, -90%), or the beta-adrenergic receptor antagonist propranalol (10 mg/kg, -35%). While these rats do not exhibit symptoms of dyskinesia per se, this rodent model does exhibit behaviors, the underlying mechanism of which is likely to be similar to that underlying L-DOPA-induced dyskinesia and may prove useful in studying the molecular and cellular mechanisms of L-DOPA-induced dyskinesia in Parkinson's disease.
Henry
B
B
Division of Neuroscience, School of Biological Sciences, University of Manchester, 1.124 Stopford Building, Manchester, M13 9PT, United Kingdom.
Crossman
A R
AR
Brotchie
J M
JM
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001971:Bromocriptine / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D007980:Levodopa / Q000494:pharmacology*; D008090:Lisuride / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008454:Mazindol / Q000378:metabolism / Q000494:pharmacology; D008732:Methoxydimethyltryptamines / Q000494:pharmacology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D016548:Prosencephalon / Q000737:chemistry / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics; D014316:Tritium; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D018765:Dopamine Uptake Inhibitors; D008732:Methoxydimethyltryptamines; D013565:Sympatholytics; D014316:Tritium; D015016:Yohimbine; D001971:Bromocriptine; D007980:Levodopa; D016627:Oxidopamine; D008454:Mazindol; D008090:Lisuride; D003000:Clonidine; D004298:Dopamine