Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: a [11C] FLB-457 and PET study

Abstract

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

Fig. 1

The gambling task is shown on the left and the control/baseline task on the right.

Fig. 2

A displays the relationship between the change in [11C] FLB-457 BP during reward in the midbrain volume in the PD patients with (closed circles) and without (open circles) PG and scores on the BIS. 95% confidence intervals for the regression line are also indicated. In B, the baseline task is represented by the unpatterned bars and the reward task is represented by the corrugated bars. The single asterisk denotes a significant difference between BP during the two scans only in the PD patients without PG at the P<0.05 level. Whiskers represent 2 standard errors.

Fig. 3

A shows the cluster revealed during the whole brain voxel-based analysis by the contrast reward>baseline, showing therefore increased BP due to gambling across all patients, superimposed on the MNI normalised brain. The cluster (k=217) peaked in the left OFC (Brodmann’s area 11) and in the left ACC (Brodmann’s area 32). B shows the main effect of group (PD with PG>PD without PG). C shows mean [11C] FLB-457 BP during the baseline and reward tasks in the PD patients with (crossed bars) and without (plain bars) PG, extracted from the whole area. Whiskers are 2 standard errors. D shows the relationship between BP in this area during the baseline scan and scores on the BIS. PD with PG is represented by closed circles and PD without PG by open circles. 95% confident limits are indicated.