Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

Abstract

We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D₂R) availability in Parkinson's disease (PD) patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [¹¹C]raclopride PET scan in an OFF medication condition for quantification of striatal D₂R availability in vivo. Parametric images of [¹¹C]raclopride non-displaceable binding potential were generated from the dynamic [¹¹C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D₂R and a mean 3.5% increase in putaminal D₂R availability compared to healthy controls. Lower caudate [¹¹C]raclopride BP_ND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D₂R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D₂Rs availability in both caudate and putamen. No associations between striatal D₂R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D₂R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D₂R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

Keywords: AIMS, Abnormal Involuntary Movement Scale; BDI-II, Beck Depression Inventory; BPND, non-displaceable binding potential; Basal ganglia; D2R, dopamine receptor type-2; Dopamine D2 receptors; Dopamine agonists; H&Y, Hoehn and Yahr staging; LED, levodopa-equivalent-dose; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PD, Parkinson's disease; PET; PET, position emission tomography; Parkinson's disease; ROI, region of interest; UPDRS, Unified Parkinson's Disease Rating Scale.

Fig. 1

Correlation between Parkinson disease duration and caudate postsynaptic dopamine receptor type-2 availability. Inverse correlation between individual caudate [¹¹C]raclopride BP_ND values and disease duration in Parkinson's disease patients (n = 68).

Fig. 2

Effect of dopamine agonist treatment (A) and presence of dyskinesia (B) on dopamine receptor type-2 receptor availability in the caudate and putamen of patients with Parkinson's disease. *p < 0.05; **p < 0.001.

Fig. 3

Graphical representation of caudate and putamen dopamine receptors type-2 (D₂R) availability in patients with Parkinson's disease. The illustration summarizes our findings together with the findings from the previous [¹¹C]raclopride PET studies (Brooks et al., 1990, Brooks et al., 1992, Leenders and Antonini, 1992, Rinne et al., 1993, Antonini et al., 1994, Antonini et al., 1997, Turjanski et al., 1997, Dentresangle et al., 1999) and shows a linear caudate reduction and a non-linear reduction of D₂R availability in the putamen as PD progresses. Also, the suppressing effect of chronic dopamine agonist treatment in striatal D₂R availability in patients with PD. PD = Parkinson's disease; D₂R = dopamine receptor type-2.