Nigrostriatal and Mesolimbic D Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors.

Stark AJ, Smith CT, Lin YC, Petersen KJ, Trujillo P, van Wouwe NC, Kang H, Donahue MJ, Kessler RM, Zald DH, Claassen DO
J Neurosci. 2018 38 (13): 3230-3239

PMID: 29483278 · PMCID: PMC5884458 · DOI:10.1523/JNEUROSCI.3082-17.2018

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with ( = 17) and without ( = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [F]fallypride, a high affinity D-like receptor ligand that can measure striatal and extrastriatal D nondisplaceable binding potential (BP). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BP In this group, self-reported severity of ICB symptoms positively correlated with midbrain D receptor BP Group differences in regional D BP relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response. The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

Copyright © 2018 the authors 0270-6474/18/383231-10$15.00/0.

MeSH Terms (17)

Aged Benzamides Compulsive Behavior Dopamine Agonists Dopamine D2 Receptor Antagonists Female Humans Limbic System Male Middle Aged Parkinson Disease Positron-Emission Tomography Radiopharmaceuticals Receptors, Dopamine D2 Receptors, Dopamine D3 Reward Substantia Nigra

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