Cabergoline and pramipexole fail to modify already established dyskinesias in an animal model of parkinsonism.
Levodopa-induced dyskinesias are one of the major limiting side effects encountered in the treatment of Parkinson's disease. Dopamine agonists of the D2 family are less prone to induce these abnormal involuntary movements (AIMs), and in some instances it has been proposed that they could counteract them once already established. As differences in the plasma half-life of a given DA agonist could be related with a greater or lesser propensity to induce or to counteract AIMs, we compared the effects of two D2 agonists (cabergoline and pramipexole) with different half-lives, and levodopa, at doses producing similar improvement in purposeful forelimb use, in rats with severe nigrostriatal lesion, previously sensitized to levodopa. The same therapeutic regime was subsequently used in pharmacologically naïve rats. We found that: (i) prior induction of AIMs by levodopa administration primes rats for the occurrence of AIMs during mono-therapy with pramipexole (but not with cabergoline); (ii) an intervening period of D2 agonist mono-therapy does not modify the severity of AIMs induced by subsequent mono-therapy with levodopa; iii. de novo treatment with D2 agonists is associated with a lower risk of AIMs (regardless of the severity of the lesion) and does not modify AIMs during subsequent mono-therapy with levodopa. An unexpected finding was that prior levodopa therapy sensitized rats to the therapeutic effects of D2 agonists given in mono-therapy. In summary, the use of the rat with nigrostriatal lesion to model relevant therapeutic conditions does not support that D2 agonists prevent the development of AIMs during subsequent levodopa mono-therapy or can revert the dysfunction underlying it.
Larramendy
Celia
C
Laboratorio de Parkinsonismo Experimental, Instituto de Investigaciones Farmacológicas, CONICET-UBA, Junín 956, 5th Floor (C1113AAD) Buenos Aires, Argentina. larramendy@ffyb.uba.ar
Taravini
Irene R E
IR
Saborido
Mariano D
MD
Ferrario
Juan E
JE
Murer
Mario G
MG
Gershanik
Oscar S
OS
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D052160:Benzothiazoles / Q000627:therapeutic use*; D000077465:Cabergoline; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004873:Ergolines / Q000627:therapeutic use*; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D008636:Mesencephalon / Q000378:metabolism; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D000077487:Pramipexole; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000978:Antiparkinson Agents; D052160:Benzothiazoles; D018492:Dopamine Antagonists; D004873:Ergolines; D007980:Levodopa; D000077487:Pramipexole; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D000077465:Cabergoline