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PET imaging of dopamine-D2 receptor internalization in schizophrenia

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A Corrigendum to this article was published on 25 July 2017

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 [11C]raclopride at baseline and two times (3–5 and 6–10 h) following 0.5 mg kg−1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HCs, we implemented a linear model with ΔBPND 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 ΔBPND (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BPND 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

  1. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235–9240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–767.

    Article  CAS  PubMed  Google Scholar 

  3. Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M . Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry 2009; 65: 1091–1093.

    Article  CAS  PubMed  Google Scholar 

  4. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997; 94: 2569–2574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R . Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999; 46: 56–72.

    Article  CAS  PubMed  Google Scholar 

  6. Skinbjerg M, Liow JS, Seneca N, Hong J, Lu S, Thorsell A et al. D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model. Neuroimage 2010; 50: 1402–1407.

    Article  CAS  PubMed  Google Scholar 

  7. Houston GC, Hume SP, Hirani E, Goggi JL, Grasby PM . Temporal characterisation of amphetamine-induced dopamine release assessed with [11C]raclopride in anaesthetised rodents. Synapse 2004; 51: 206–212.

    Article  CAS  PubMed  Google Scholar 

  8. Ginovart N, Wilson AA, Houle S, Kapur S . Amphetamine pretreatment induces a change in both D2-Receptor density and apparent affinity: a [11C]raclopride positron emission tomography study in cats. Biol Psychiatry 2004; 55: 1188–1194.

    Article  CAS  PubMed  Google Scholar 

  9. Narendran R, Slifstein M, Hwang DR, Hwang Y, Scher E, Reeder S et al. Amphetamine-induced dopamine release: duration of action as assessed with the D2/3 receptor agonist radiotracer (−)-N-[(11)C]propyl-norapomorphine ([11C]NPA) in an anesthetized nonhuman primate. Synapse 2007; 61: 106–109.

    Article  CAS  PubMed  Google Scholar 

  10. Narendran R, Hwang DR, Slifstein M, Hwang Y, Huang Y, Ekelund J et al. Measurement of the proportion of D2 receptors configured in state of high affinity for agonists in vivo: a positron emission tomography study using [11C]N-propyl-norapomorphine and [11C]raclopride in baboons. J Pharmacol Exp Ther 2005; 315: 80–90.

    Article  CAS  PubMed  Google Scholar 

  11. Cardenas L, Houle S, Kapur S, Busto UE . Oral d-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET. Synapse 2004; 51: 27–31.

    Article  CAS  PubMed  Google Scholar 

  12. Laruelle M . Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 2000; 20: 423–451.

    Article  CAS  PubMed  Google Scholar 

  13. Laruelle M . The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 2000; 31: 371–384.

    Article  CAS  PubMed  Google Scholar 

  14. Ginovart N . Imaging the dopamine system with in vivo [11C]raclopride displacement studies: understanding the true mechanism. Mol Imaging Biol 2005; 7: 45–52.

    Article  PubMed  Google Scholar 

  15. Guo N, Guo W, Kralikova M, Jiang M, Schieren I, Narendran R et al. Impact of D2 receptor internalization on binding affinity of neuroimaging radiotracers. Neuropsychopharmacology 2010; 35: 806–817.

    Article  CAS  PubMed  Google Scholar 

  16. Quelch DR, Withey SL, Nutt DJ, Tyacke RJ, Parker CA . The influence of different cellular environments on PET radioligand binding: an application to D2/3-dopamine receptor imaging. Neuropharmacology 2014; 85: 305–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chugani DC, Ackermann RF, Phelps ME . In vivo [3H]spiperone binding: evidence for accumulation in corpus striatum by agonist-mediated receptor internalization. J Cereb Blood Flow Metab 1988; 8: 291–303.

    Article  CAS  PubMed  Google Scholar 

  18. Skinbjerg M, Ariano MA, Thorsell A, Heilig M, Halldin C, Innis RB et al. Arrestin3 mediates D(2) dopamine receptor internalization. Synapse 2009; 63: 621–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Laruelle M, Guo N, Guo W, Jiang M, Schieren I, Abi-Dargham A et al. Impact of dopamine D2 receptor internalization on binding parameters of D2 PET radiotracers. Neuroimage 2008; 41: T36–T36.

    Article  Google Scholar 

  20. Narendran R, Hwang DR, Slifstein M, Talbot PS, Erritzoe D, Huang Y et al. In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (−)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse 2004; 52: 188–208.

    Article  CAS  PubMed  Google Scholar 

  21. Hwang DR, Narendran R, Laruelle M . Positron-labeled dopamine agonists for probing the high affinity states of dopamine subtype 2 receptors. Bioconjug Chem 2005; 16: 27–31.

    Article  CAS  PubMed  Google Scholar 

  22. Papaleo F, Weinberger DR . Dysbindin and Schizophrenia: it's dopamine and glutamate all over again. Biol Psychiatry 2011; 69: 2–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN et al. Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 2012; 17: 85–98.

    Article  CAS  PubMed  Google Scholar 

  24. Schubert KO, Focking M, Prehn JH, Cotter DR . Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder? Mol Psychiatry 2012; 17: 669–681.

    Article  CAS  PubMed  Google Scholar 

  25. Beaulieu JM . A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health. J Psychiatry Neurosci 2012; 37: 7–16.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ji Y, Yang F, Papaleo F, Wang HX, Gao WJ, Weinberger DR et al. Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci USA 2009; 106: 19593–19598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Su P, Li S, Chen S, Lipina TV, Wang M, Lai TK et al. A dopamine D2 receptor–DISC1 protein complex may contribute to antipsychotic-like effects. Neuron 2014; 84: 1302–1316.

    Article  CAS  PubMed  Google Scholar 

  28. Appelbaum PS, Grisso T . The MacArthur Treatment Competence Study. I: Mental illness and competence to consent to treatment. Law Hum Behav 1995; 19: 105–126.

    Article  PubMed  Google Scholar 

  29. Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994; 51: 849–859; discussion 844–863.

    Article  PubMed  Google Scholar 

  30. Hollingshead AB . Four factor index of social status. Working paper published by the author.: New Haven, Connecticut, 1975.

  31. Mason OJ, Morgan CJ, Stefanovic A, Curran HV . The psychotomimetic states inventory (PSI): measuring psychotic-type experiences from ketamine and cannabis. Schizophr Res 2008; 103: 138–142.

    Article  PubMed  Google Scholar 

  32. Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.

    Article  CAS  PubMed  Google Scholar 

  33. Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR et al. 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: 1034–1057.

    Article  CAS  PubMed  Google Scholar 

  34. Lammertsma AA, Hume SP . Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4 (Part 1): 153–158.

    Article  CAS  PubMed  Google Scholar 

  35. Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry 2013; 18: 909–915.

    Article  CAS  PubMed  Google Scholar 

  36. Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M et al. Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci USA 2011; 108: 18488–18493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tan HY, Chen AG, Chen Q, Browne LB, Verchinski B, Kolachana B et al. Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. Mol Psychiatry 2012; 17: 1007–1016.

    Article  CAS  PubMed  Google Scholar 

  38. Kotowski SJ, Hopf FW, Seif T, Bonci A, von Zastrow M . Endocytosis promotes rapid dopaminergic signaling. Neuron 2011; 71: 278–290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Eichel K, Jullie D, von Zastrow M . Beta-arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 2016; 18: 303–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Irannejad R, Kotowski SJ, von Zastrow M . Investigating signaling consequences of GPCR trafficking in the endocytic pathway. Methods Enzymol 2014; 535: 403–418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Laruelle M, Abi-Dargham A . Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol 1999; 13: 358–371.

    Article  CAS  PubMed  Google Scholar 

  42. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000; 97: 8104–8109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Smith CT, Dang LC, Cowan RL, Kessler RM, Zald DH . Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine. Neuropharmacology 2016; 108: 394–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Smith CT, Weafer J, Cowan RL, Kessler RM, Palmer AA, de Wit H et al. Individual differences in timing of peak positive subjective responses to d-amphetamine: relationship to pharmacokinetics and physiology. J Psychopharmacol 2016; 30: 330–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Angrist B, Corwin J, Bartlik B, Cooper T . Early pharmacokinetics and clinical effects of oral d-amphetamine in normal subjects. Biol Psychiatry 1987; 22: 1357–1368.

    Article  CAS  PubMed  Google Scholar 

  46. Slifstein M, Kegeles LS, Xu X, Thompson JL, Urban N, Castrillon J et al. Striatal and extrastriatal dopamine release measured with PET and [(18)F] fallypride. Synapse 2010; 64: 350–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947–1954.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Funding for this study was provided by Grant R21 MH099509 from the National Institute of Mental Health (NIMH) to Dr Abi-Dargham. Dr Weinstein was supported by a T32 Grant from NIMH (MH018870). Dr van de Giessen was supported by a Rubicon grant from the Netherlands Organization for Scientific Research (825.12.009). We would also like to acknowledge the contributions of Dr Skinbjerg in early stages of project development, Rassil Ghazzoui in participant recruitment, Seth Baker in data collection, Nadia-Tina Dandan in data entry and Dr Cassidy in early stages of data interpretation.

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Authors and Affiliations

  1. Department of Psychiatry, Stony Brook University School of Medicine, SUNY at Stony Brook, Health Sciences T10-041-L, Stony Brook, NY, USA

    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

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  1. J J Weinstein
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  2. E van de Giessen
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  4. X Xu
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Correspondence to J J Weinstein.

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Weinstein, J., van de Giessen, E., Rosengard, R. et al. PET imaging of dopamine-D2 receptor internalization in schizophrenia. Mol Psychiatry 23, 1506–1511 (2018). https://doi.org/10.1038/mp.2017.107

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