Functional consequences of dopaminergic degeneration : Clinical and experimental studies using a novel stabilizer of dopaminergic systems

Sammanfattning: Since the introduction of levodopa for the treatment of Parkinson's disease (PD) 30 yearsago, the emergence of motor complications, such as levodopa-induced dyskinesias (LID), hasbeen a major clinical problem in advanced stages of the disease. Clinical and preclinical studieshave revealed a number of functional changes in the dopaminergic system that may be ofimportance for the emergence of LIDs. Such changes include postsynaptic alterations indopamine (DA), receptor function, and characteristic modifications at the presynaptic level.The presynaptic structural integrity and function of the dopaminergic system were studied in patients with different stages of PD using positron emission tomography (PET) and the radiotracers L-[11C]DOPA and [11C]CIT-FE. In early PD a marked reduction in striatal L-[11C]DOPA influx rate was observed after therapeutic doses of antiparkinsonian medication. Nosuch changes were observed in advanced PD, indicating a diminished inhibitory feedbackregulation. Moreover, the L-[11C]DOPA/[11C]CIT-FE ratio, a measure of dopamine transportercorrected dopamine synthesis capacity, increased in early PD patients as compared with healthyvolunteers, indicating an up-regulation in DA turnover in residual dopaminergic nerveterminals.Furthermore, the effects of (-)-OSU6162 ((S)-(-)-3-methylsulfonyllhenyl-1-propylpiperidine), a novel stabilizer of dopaminergic systems, were investigated using PET andanimal models of PD. It was concluded that (-)-OSU6162 may exhibit postsynapticantagonizing properties on DA D2 receptor function. The compound also exhibited somepotentiating effects on DA D1 receptor function. (-)-OSU6162 was highly efficient in inhibitingLIDs in parkinsonian monkeys and DA D2 receptor agonist-induced rotational behavior inunilaterally DA-lesioned monkeys, without inducing a concomitant return to hypokinesia. Thecompound was also efficacious in decreasing choreatic events in one patient with Huntington'sdisease (HD).In summary, changes in presynaptic dopaminergic function occur with disease progression inPD. Such changes may indirectly contribute to the induction of levodopa-induced motorcomplications. Because of its stabilizing effect on dopaminergic systems, the novel compound(-)-OSU6162 might prove to have beneficial effects as an adjuvant treatment in advanced PDand other disorders charactererized by dysregulated dopaminergic systems.