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.

Imaging insights into basal ganglia function, Parkinson's disease, and dystonia

“…The gamblers, by contrast, showed a significant agonist-induced reduction in rCBF. Results of a subsequent PET study using the extrastriatal dopamine receptor ligand 11 C-FLB-457 59 showed significant abnormalities in D 2 receptor binding in the orbitofrontal cortex and anterior cingulate cortex in patients with Parkinson's disease with pathological gambling compared with control patients with Parkinson's disease, again supporting the key role of prefrontal control in the development of ICDs (figure 4).…”

Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment

“…Patients with Parkinson's disease who are exposed to non-physiological dopaminergic stimulation are at high risk of developing a range of behavioural addictions or impulse control disorders. 88,89,91,122,154 By contrast, patients are at risk of developing apathy-an…”

“…Modulation of the meso corticolimbic networks by dopaminergic drugs (especially dopamine D2 and D3 receptor agonists) with relatively high affi nity for the mesolimbic system 119 is also implicated in the appetitive drive to perform pleasurable activities (eg, creativity or hobbies), 120,121 which can lead (at extreme levels) to behavioural addictions and impulse control disorders. 88,89,122 Decrease of dopaminergic agonists in the context of STN-DBS, or a switch to non-pulsatile treatment with levodopa, results in disap pearance of the increased drive for artistic creativity 120,121 and the emergence of severe apathy. 120 This process can at least partly be reversed after a careful titration of the dose of the dopamine agonist.…”

Molecular imaging and neural networks in impulse control disorders in Parkinson's disease

“…Lower receptor density was also associated with a higher striatal release of dopamine. Subsequently, Ray et al [27] The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 binding was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG, and binding in this region was also correlated with impulsivity.…”

“…Cilia et al [24], Vriend et al [25] Low midbrain dopamine autoreceptor function Lack of homeostatic control over striatal DA release, causing increased sensitivity to rewards/propensity for impulsivity Ray et al [27], Cole et al [28] Altered cortical and striatal responses to feedback when on dopamine agonists…”