Cabergoline and pramipexole fail to modify already established dyskinesias in an animal model of parkinsonism

LARRAMENDY C; TARAVINI IRE; SABORIDO MD; FERRARIO JE; MURER MG; GERSHANIK OS

BEHAVIOURAL BRAIN RESEARCH

Elsevier

Año: 2008 vol. 194 p. 44 - 51

0166-4328

Abnormal involuntary movements (AIMs) stand as a major problem of pharmacological therapy in Parkinson’s disease. It is believed that D2 agonists are less prone to induce AIMs and that they could counteract AIMs induced by levodopa. However, it turned out to be challenging to empirically support these contentions as, in the clinical setting, it is difficult to match the clinical efficacy of the treatments that are being compared or to warrant that patients have similar disease severity and progression. We tried to circumvent these limitations by comparing the effects of D2 agonists (cabergoline and pramipexole) and levodopa, at doses producing similar improvement in purposeful forelimb use, in rats with similar behavioral impairment induced by severe nigrostriatal lesions. We found that: i. de novo treatment with D2 agonists is associated with a low risk of AIMs (regardless of the severity of the lesion) and does not modify AIMs during subsequent mono-therapy with levodopa; ii. prior induction of AIMs by levodopa administration primes rats for occurrence of AIMs during mono-therapy with pramipexole (but not with cabergoline); iii. an intervening period of D2 agonist mono-therapy does not modify the severity of AIMs induced by 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, this first use of the rat with nigrostriatal lesion to model relevant therapeutic conditions do not support that D2 agonists prevent the development of AIMs during subsequent levodopa mono-therapy or can overturn the dysfunction underlying it.