PET Imaging of Dopamine-D2 Receptor Internalization in Schizophrenia

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2017 May 17

PMID 28507321

Citations 9

Authors

J J Weinstein

E van de Giessen

R J Rosengard

X Xu

N Ojeil

G Brucato

R B Gil

L S Kegeles

M Laruelle

M Slifstein

A Abi-Dargham

Affiliations

Soon will be listed here.

Abstract

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BP) and derived percent reduction from baseline (ΔBP) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BP to baseline differed between SZ and HCs, we implemented a linear model with ΔBP as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBP (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BP to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

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References

Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles L, Laruelle M . Baseline and amphetamine-stimulated dopamine activity are related in drug-naïve schizophrenic subjects. Biol Psychiatry. 2009; 65(12):1091-3. DOI: 10.1016/j.biopsych.2008.12.007. View

Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang D . Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab. 2001; 21(9):1034-57. DOI: 10.1097/00004647-200109000-00002. View

Tan H, Chen A, Chen Q, Browne L, Verchinski B, Kolachana B . Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. Mol Psychiatry. 2011; 17(10):1007-16. PMC: 3449232. DOI: 10.1038/mp.2011.91. View

Smith C, Dang L, Cowan R, Kessler R, Zald D . Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine. Neuropharmacology. 2016; 108:394-402. PMC: 4912942. DOI: 10.1016/j.neuropharm.2016.05.004. View

Breier A, Su T, Saunders R, Carson R, Kolachana B, de Bartolomeis A . Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A. 1997; 94(6):2569-74. PMC: 20129. DOI: 10.1073/pnas.94.6.2569. View

Smith C, Weafer J, Cowan R, Kessler R, Palmer A, de Wit H . Individual differences in timing of peak positive subjective responses to d-amphetamine: Relationship to pharmacokinetics and physiology. J Psychopharmacol. 2016; 30(4):330-43. PMC: 5049703. DOI: 10.1177/0269881116631650. View

Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley J . Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry. 2010; 17(1):85-98. PMC: 3388848. DOI: 10.1038/mp.2010.106. View

Eichel K, Jullie D, von Zastrow M . β-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol. 2016; 18(3):303-10. PMC: 4767649. DOI: 10.1038/ncb3307. View

Guo N, Guo W, Kralikova M, Jiang M, Schieren I, Narendran R . Impact of D2 receptor internalization on binding affinity of neuroimaging radiotracers. Neuropsychopharmacology. 2009; 35(3):806-17. PMC: 2813939. DOI: 10.1038/npp.2009.189. View

10.

Hwang D, Narendran R, Laruelle M . Positron-labeled dopamine agonists for probing the high affinity states of dopamine subtype 2 receptors. Bioconjug Chem. 2005; 16(1):27-31. DOI: 10.1021/bc049834n. View

11.

Su P, Li S, Chen S, Lipina T, Wang M, Lai T . A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects. Neuron. 2014; 84(6):1302-16. DOI: 10.1016/j.neuron.2014.11.007. View

12.

Ji Y, Yang F, Papaleo F, Wang H, Gao W, Weinberger D . Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci U S A. 2009; 106(46):19593-8. PMC: 2780743. DOI: 10.1073/pnas.0904289106. View

13.

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles L . Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000; 97(14):8104-9. PMC: 16677. DOI: 10.1073/pnas.97.14.8104. View

14.

Bray N, Preece A, Williams N, Moskvina V, Buckland P, Owen M . Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet. 2005; 14(14):1947-54. DOI: 10.1093/hmg/ddi199. View

15.

Chugani D, Ackermann R, Phelps M . In vivo [3H]spiperone binding: evidence for accumulation in corpus striatum by agonist-mediated receptor internalization. J Cereb Blood Flow Metab. 1988; 8(3):291-303. DOI: 10.1038/jcbfm.1988.64. View

16.

Appelbaum P, Grisso T . The MacArthur Treatment Competence Study. I: Mental illness and competence to consent to treatment. Law Hum Behav. 1995; 19(2):105-26. DOI: 10.1007/BF01499321. View

17.

Slifstein M, Kegeles L, Xu X, Thompson J, Urban N, Castrillon J . Striatal and extrastriatal dopamine release measured with PET and [(18)F] fallypride. Synapse. 2009; 64(5):350-62. PMC: 2840194. DOI: 10.1002/syn.20734. View

18.

Quelch D, Withey S, Nutt D, Tyacke R, Parker C . The influence of different cellular environments on PET radioligand binding: an application to D2/3-dopamine receptor imaging. Neuropharmacology. 2014; 85:305-13. PMC: 4109028. DOI: 10.1016/j.neuropharm.2014.05.040. View

19.

Allen J, Yost J, Setola V, Chen X, Sassano M, Chen M . Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci U S A. 2011; 108(45):18488-93. PMC: 3215024. DOI: 10.1073/pnas.1104807108. View

20.

Papaleo F, Weinberger D . Dysbindin and Schizophrenia: it's dopamine and glutamate all over again. Biol Psychiatry. 2010; 69(1):2-4. PMC: 3021467. DOI: 10.1016/j.biopsych.2010.10.028. View