Dataset Information

Striatal D1 and D2 receptor availability are selectively associated with eye-blink rates after methylphenidate treatment.

ABSTRACT: Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between blink rates, measured after oral placebo) (PL) and after a challenge with oral methylphenidate (MP; 60 mg) and striatal D1 receptor (D1R) (measured at baseline) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R ([¹¹C]NNC112) (BL-D1R) and D2R availability ([¹¹C]raclopride) after PL (PL-D2R) and after MP (MP-D2R) were quantified in the striatum as non-displaceable binding potential. MP reduced the number of blinks and increased the time participants kept their eyes open. Correlations with dopamine receptors were only significant for the eye blink measures obtained after MP; being positive for BL-D1R in putamen and MP-D2R in caudate (PL-D2R were not significant). MP-induced changes in blink rates (PL minus MP) were negatively correlated with BL-D1R in caudate and putamen. Our findings suggest that eye blink measures obtained while stressing the dopamine system might provide a more sensitive behavioral biomarker of striatal D1R or D2R in healthy volunteers than that obtained at baseline or after placebo.

SUBMITTER: Demiral SB

PROVIDER: S-EPMC9513088 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Striatal D1 and D2 receptor availability are selectively associated with eye-blink rates after methylphenidate treatment.

Demiral Şükrü B ŞB Manza Peter P Biesecker Erin E Wiers Corinde C Shokri-Kojori Ehsan E McPherson Katherine K Dennis Evan E Johnson Allison A Tomasi Dardo D Wang Gene-Jack GJ Volkow Nora D ND

Communications biology 20220926 1

Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between blink rates, measured after oral placebo) (PL) and after a challenge with oral methylphenidate (MP; 60 mg) and striatal D1 receptor (D1R) (measured at baseline) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R ([<sup>11</sup>C]NNC112) (BL-D1R) and D2R availabi ...[more]

PMID: 36163254

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Project description:Dopamine signaling plays a critical role in shaping brain functional network organization and behavior. Prominent theories suggest the relative expression of D1- to D2-like dopamine receptors shapes excitatory versus inhibitory signaling, with broad consequences for cognition. Yet it remains unknown how the balance between cortical D1R versus D2R signaling coordinates the activity and connectivity of functional networks in the human brain. To address this, we collected three PET scans and two fMRI scans in 36 healthy adults (13 female/23 male; average age 43 ± 12 years), including a baseline D1R PET scan and two sets of D2R PET scans and fMRI scans following administration of either 60 mg oral methylphenidate or placebo (two separate days, blinded, order counterbalanced). The drug challenge allowed us to assess how pharmacologically boosting dopamine levels alters network organization and behavior in association with D1R-D2R ratios across the brain. We found that the relative D1R-D2R ratio was significantly greater in high-level association cortices than in sensorimotor cortices. After stimulation with methylphenidate compared to placebo, brain activity (as indexed by the fractional amplitude of low frequency fluctuations) increased in association cortices and decreased in sensorimotor cortices. Further, within-network resting state functional connectivity strength decreased more in sensorimotor than association cortices following methylphenidate. Finally, in association but not sensorimotor cortices, the relative D1R-D2R ratio (but not the relative availability of D1R or D2R alone) was positively correlated with spatial working memory performance, and negatively correlated with age. Together, these data provide a framework for how dopamine-boosting drugs like methylphenidate alter brain function, whereby regions with relatively higher inhibitory D2R (i.e., sensorimotor cortices) tend to have greater decreases in brain activity and connectivity compared to regions with relatively higher excitatory D1R (i.e., association cortices). They also support the importance of a balanced interaction between D1R and D2R in association cortices for cognitive function and its degradation with aging.

Project description:Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 "Translating Ribosome Affinity Purification" (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.

Dataset Information

Striatal D1 and D2 receptor availability are selectively associated with eye-blink rates after methylphenidate treatment.

Publications

Striatal D1 and D2 receptor availability are selectively associated with eye-blink rates after methylphenidate treatment.

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