Nigrostriatal and Mesolimbic D2/3Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors

Adam J. Stark, Christopher T. Smith, Ya-Chen Lin, Kalen J. Petersen, Paula Trujillo, Nelleke C. van Wouwe, Hakmook Kang, Manus J. Donahue, Robert M. Kessler, David H. Zald, Daniel O. Claassen
2018 Journal of Neuroscience  
The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D 2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D 2 -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 2/3
more » ... 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 (n ϭ 17) and without (n ϭ 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [ 18 F]fallypride, a high affinity D 2 -like receptor ligand that can measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). Striatal differences between ICBϩ/ ICBϪ patients localized to the ventral striatum and putamen, where ICBϩ subjects had reduced BP ND . In this group, self-reported severity of ICB symptoms positively correlated with midbrain D 2/3 receptor BP ND . Group differences in regional D 2/3 BP ND relationships were also notable: ICBϩ (but not ICBϪ) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BP ND s. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D 2/3 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 ICBϩ 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 ICBϩ patients using positron emission tomography with [18F]fallypride, allowing quantification of D 2/3 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 2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.
doi:10.1523/jneurosci.3082-17.2018 pmid:29483278 fatcat:g4ohj3k4efek5cb5i7s5ohtbya