Mesolimbic Dopaminergic Neural Changes in Relation to the Impulsive Compulsive Behaviors in patients with Parkinson's disease

Abstract

Introduction: Impulsive compulsive behavior disorders (ICB) frequently occurs in patients with Parkinsons disease (PD) on long-term dopamine replacement therapy. The category of ICB in PD includes addictive behaviors like impulse control disorders (ICD), such as pathological gambling, compulsive shopping, hypersexuality, binge eating, and compulsive use of dopaminergic drugs (dopamine dysregulation syndrome=DDS), and an aimless repetitive stereotyped behaviors called as punding. The prevalence of ICB is reported to be 10 to 14% for ICD, and up to 30% for ICB including DDS and punding in PD patients taking chronic dopaminergic drugs. These figures are significantly higher than those in drug-naïve PD and general populations. The strongest risk factor for ICB is dopaminergic drugs, especially dopamine agonists. However not all patients taking dopamine agonists develop ICB. Thus identification of other predisposing factors is an interesting issue for clinical perspective as well as for pathophysiological research. Methods: First, genetic predisposing factors to ICB were identified by analyzing highly relevant genetic variants in a PD cohort (N=404) and in 559 age-matched healthy controls. Genotyping was performed for variants of the DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.366C>G, c.2664C>T and c.-200T>G, the promoter region of the serotonin transporter gene (5-HTTLPR). Second, characteristic dopaminergic neural changes associated with the appearance of ICB were evaluated. In 26 PD patients and 10 age-matched healthy controls, a functional in-vivo imaging using dynamic N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane ([18F]FP-CIT) positron emission tomography (PET) was performed. The binding potential differences represent presynaptic dopaminergic neural changes which may be related to degenerative process or to plastic change induced by chronic dopaminergic therapy or by the ICB itself. Binding potentials of [18F]FP-CIT were estimated at putamen, caudate, nucleus accumbens (NAC), amygdala (AMG), orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (VMPFC) using the Logan method. Whole brain parametric maps of [18F]FP-CIT were also analyzed. Results: The ICB was found in 14.4% in this Korean PD cohort. Variants of DRD2 and 5-HTTLPR were not associated with the risk of developing ICB. However, the AA genotype of DRD3 p.S9G and the CC genotype of GRIN2B c.366C>G were more frequent in patients with ICB than in unaffected patients (odds ratio [OR] = 2.21, P = 0.0094

and 2.14, P = 0.0087, after adjusting for age and sex). After controlling for clinical variables in the multivariate analysis, carriage of either AA genotype of DRD3 or CC genotype of GRIN2B was identified as an independent risk factor for ICB (adjusted OR = 2.57, P = 0.0087). In [18F]FP-CIT PET analysis, the binding potential at VMPFC was significantly higher in the two PD groups than in the healthy controls. The ratios of extrastriatal to putaminal binding potentials were approximately 3 times higher in PD than controls. In the comparison between the PD ICB and non-ICB patients, the ICB group showed significantly lower binding potentials at the left NAC and higher values at the right VMPFC compared with those free of ICB. The binding potential ratios of the right VMPFC/putamen, were significantly correlated with the magnitude of ICB behaviors. In the parametric analysis between the two PD groups, there was reduced [18F]FP-CIT uptakes at both ventral striatal regions in PD ICB group. In the putaminal re-normalized parametric maps, PD ICB group showed significantly higher uptakes at the left insular and right posterior cingulate cortex and lower uptakes at both ventral pallidums than the non-ICB group. Conclusions: PD patients had an intrinsic pathological condition toward hyper-dopamine content in the mesolimbic system. Dopaminergic drug therapy would potentiate this condition resulting in PD patients predisposed to ICB. Mesolimbic dopaminergic system plays an important role in reward learning, and interestingly, genetic variants actively involved in this system were significantly associated with the ICB risk in PD. The in-vivo dopaminergic neural imaging revealed that activation of areas regarding reward sensitive decision making and interoceptive urges for addictive behaviors, and less dopaminergic modulation to areas responsible for the processing of convergent signals from diverse rewards, were characteristic features in PD ICB patients. Further works on the impact of chronic dopaminergic drug therapy, especially dopamine agonists, on the mesolimbic and other extrastriatal systems could provide a further insight into a mechanism of medication-related ICB in PD.