Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia

Radioligand binding assays to rat striatal dopamine D-1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D-1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D-1 receptors heteromerize with dopamine D-3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D-3 and D-1-D-3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-l-alanine (l-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D-3 agonist led in dyskinetic, but not in lesioned or l-DOPA-treated rats, to a higher dopamine sensitivity. Upon D-3-receptor activation, the affinity of agonists for binding to the right striatal D-1 receptor increased. Excess dopamine coming from l-DOPA medication likely activates D-3 receptors thus making right and left striatal D-1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D-1 receptor-mediated neurotransmission.