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.

Introduction

Symptomatic relief of motor symptoms in Parkinson's disease (PD) is achieved by increasing endogenous dopamine (DA) levels using levodopa, or by synthetic activation of DA receptors using DA agonists. Dopamine agonists in particular may contribute to the development of impulse control disorders (ICDs) in about 13% of PD patients (Voon et al., 2006, Weintraub et al., 2010). These include pathological gambling (PG), hypersexuality, compulsive shopping and compulsive eating, and are considered as behavioural addictions with epidemiology and phenomenology similar to substance addiction (Potenza, 2008, Ray and Strafella, 2010, Voon et al., 2011a, Voon et al., 2011c). Neurobiological commonalities in DA and 5HT neurotransmitter systems have also been noted (Leeman and Potenza, 2012, Zack and Poulos, 2009).

Proposed mechanisms for the development of an ICD in PD include excessive dopaminergic stimulation of the mesolimbic pathway (Cools et al., 2003), and interference with reward based learning by tonically occupying post-synaptic DA receptors (van Eimeren et al., 2009, van Eimeren et al., 2010, Voon et al., 2010). The later is associated with decreased blood oxygen level dependent (BOLD) activity in the orbitofrontal (OFC) and anterior cingulate cortex (ACC) (Voon et al., 2011b). These areas are also hypoactive in substance addiction, associated with decreased striatal D2 receptor availability measured with [11C] Raclopride and PET (Goldstein and Volkow, 2011, Volkow et al., 2011, Volkow et al., 2012).

The impulsive personality trait represents a significant risk factor for the development of an ICD in PD (Voon and Dalley, 2011). In the non-PD population, impulsive individuals have greater amphetamine-induced release of DA in the striatum (Buckholtz et al., 2010), an abnormality also seen in PD patients with PG in response to monetary reward (Steeves et al., 2009). Buckholtz et al. (2010), using the PET ligand [18F] Fallypride, also found that trait impulsivity was negatively associated with binding to DA D2/3 receptors in the midbrain. DA receptors in this region are dominated by autoreceptors (Khan et al., 1998), which function to limit striatal DA release following reward. This suggests that midbrain autoreceptors influence individuals' propensity for impulsivity, and opens the possibility that excessive striatal DA release following gambling rewards in PD patients with PG, shown in Steeves et al. (2009), stems from reduced control over striatal DA by midbrain autoreceptors.

DA function in the cortex may also contribute to the impulsive personality trait. Genetic studies suggest that polymorphisms of the catechol-O-methyltransferase (COMT) gene, associated with increased rate of synaptic dopamine catabolism in the prefrontal cortex (PFC), and therefore reduced basal DA levels in these areas, are more frequent in more impulsive people (Paloyelis et al., 2010). To the best of our knowledge, no studies have investigated extrastriatal abnormalities in PD patients with PG.

Here were report the results of our PET and [11C] FLB-457 study, a radiotracer with high affinity for DA D2/3 receptors, and therefore sensitivity to extrastriatal, but not striatal D2/3 receptors (Olsson et al., 1999), showing midbrain and PFC dopaminergic differences in PD patients with and without PG.