The mechanisms underlying
dopamine agonist-induced
dyskinesia in
Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by
6-hydroxydopamine are more likely to show
dyskinesia during chronic treatment with unselective
dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing
dyskinesia. As a first step towards disclosing
drug-induced brain activation in
dyskinesia, we examined the effects of
dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with
dopamine agonists. The unselective agonist
apomorphine and the selective D1/D5 agonist
SKF-81297 induced strong forelimb
dyskinesia (FD) and axial
dystonia and increased BOLD signal in the denervated striatum. Besides,
SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist
quinpirole, which induced mild
dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and
dyskinesia comes from a direct correlation between scores of FD and magnitude of
drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose
dyskinesia in
parkinsonism.