Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover

Abstract

Motor fluctuations are a major disabling complication in the treatment of Parkinson's disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinson's disease with a follow-up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed "wearing-off" fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, 1 hour post-levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent "wearing-off" phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa-related motor complications.

Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition

“…This drug is a peripherally selective D 2 antagonist used to combat the peripheral effects of apomorphine. The time between scans was to allow for the decay of [ 11 C]raclopride and the clearance of apomorphine (de la Fuente-Fernández et al, 2001).…”

“…This drug is a peripherally selective D 2 antagonist used to combat the peripheral effects of apomorphine. The time between scans was to allow for the decay of [ 11 C]raclopride and the clearance of apomorphine (de la Fuente-Fernández et al, 2001).All PET scans were performed in three-dimensional mode using an ECAT 953B/31 tomograph (Siemens Canada/CTI Knoxville, TN, U.S.A.). Attenuation correction was achieved by performing a 15-minute transmission scan using 68 Ge rods.…”

“…For instance, a relative failure to down-regulate dopamine synthesis and release in response to apomorphine may contribute to the steeper dose-response curve noted in patients with more severe PD as compared with those with less severe PD. This is because in patients with relatively intact autoregulatory function, a decrease in synaptic dopamine would partially offset the stimulatory effect of apomorphine, whereas this would not occur in patients lacking autoregulatory function.Although decreased autoregulatory function may have some benefits, it also may contribute to the increase in dopamine turnover (Abercrombie et al, 1990;Calne and Zigmond, 1991) that has been noted to accompany PD progression (Tedroff et al, 1996) and that the authors have observed to be associated with the development of motor fluctuations (de la Fuente-Fernández et al, 2000, 2001. Furthermore, it may contribute to the development of dyskinesias.…”

Imaging in Parkinson's Disease

“…In the placebo group, reductions in striatal [ 11 C]raclopride binding were comparable to that observed in PD patients that received a therapeutic dose of apomorphine (de la FuenteFernandez, Lim, et al, 2001;de la Fuente-Fernandez, Lu, et al, 2001;. PD patients in the placebo group showed a decrease in [ 11 C]raclopride binding in the ventral striatum after placebo as compared to baseline.…”

Tyramine excites rat subthalamic neurons in vitro by a dopamine-dependent mechanism

“…However, levodopa treatment and the subsequent metabolism of dopamine increase the levels of many trace amines including tyramine (Edwards et al, 1981;Boulton and Quan, 1970). Furthermore, the loss of dopamine uptake sites in severe Parkinson's disease causes levodopa treatment to increase the levels of dopamine and dopamine metabolites to a much greater extent compared to levels produced by levodopa in control subjects (de la Fuente-Fernández et al, 2001;Abercrombie et al, 1990). From the standpoint of efficacy, it has been suggested that elevated levels of trace amines might contribute to the superiority of levodopa over synthetic dopamine agonist treatment of Parkinson's disease ).…”