Skip to main content
SpringerLink
Log in

Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [11C]NNC112

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder.

Objectives

The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD.

Methods

We used positron emission tomography (PET) and the radiotracer [11C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BPF, BPND, and BPP) were calculated for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addition Test (PASAT).

Results

There were no significant group differences in PFC BP. BPF and BPP in the medial PFC were significantly negatively related to PASAT performance (r s  = −0.551, p = .022 and r s  = −0.488, p = .047, respectively), but BP was not related to 2-back performance.

Conclusions

In contrast to what has been found in schizophrenia, SPD was not associated with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was associated with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiological feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abi-Dargham A, Martinez D, Mawlawi O, Simpson N, Hwang DR, Slifstein M, Anjilvel S, Pidcock J, Guo NN, Lombardo I, Mann JJ, Van Heertum R, Foged C, Halldin C, Laruelle M (2000) Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility. J Cereb Blood Flow Metab 20:225–243

    Article  PubMed  CAS  Google Scholar 

  • Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22:3708–3719

    PubMed  CAS  Google Scholar 

  • Abi-Dargham A, Kegeles LS, Zea-Ponce Y, Mawlawi O, Martinez D, Mitropoulou V, O’Flynn K, Koenigsberg HW, Van Heertum R, Cooper T, Laruelle M, Siever LJ (2004) Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide. Biol Psychiatry 55:1001–1006

    Article  PubMed  CAS  Google Scholar 

  • Abi-Dargham A, Xu X, Thompson JL, Gil R, Kegeles LS, Urban N, Narendran R, Hwang DR, Laruelle M, Slifstein M (2012) Increased prefrontal cortical D(1) receptors in drug naive patients with schizophrenia: a PET study with [(11)C]NNC112. J Psychopharmacol 26:794–805

    Article  PubMed  CAS  Google Scholar 

  • APA (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS (1994) Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 116:143–151

    Article  CAS  Google Scholar 

  • Barch DM, Mitropoulou V, Harvey PD, New AS, Silverman JM, Siever LJ (2004) Context-processing deficits in schizotypal personality disorder. J Abnorm Psychol 113:556–568

    Article  PubMed  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Ser B 57:289–300

    Google Scholar 

  • Cohen JD, Perlstein WM, Braver TS, Nystrom LE, Noll DC, Jonides J, Smith EE (1997) Temporal dynamics of brain activation during a working memory task. Nature 386:604–608

    Article  PubMed  CAS  Google Scholar 

  • Ekelund J, Slifstein M, Narendran R, Guillin O, Belani H, Guo NN, Hwang Y, Hwang DR, Abi-Dargham A, Laruelle M (2007) In vivo DA D(1) receptor selectivity of NNC 112 and SCH 23390. Mol Imaging Biol 9:117–125

    Article  PubMed  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Williams JBW (1994) Structured Clinical Interview for DSM-IV Axis-I Disorders, Version 2.0. Biometrics Research New York State Psychiatric Institute, New York

    Google Scholar 

  • Fischer H, Nyberg L, Karlsson S, Karlsson P, Brehmer Y, Rieckmann A, MacDonald SW, Farde L, Backman L (2010) Simulating neurocognitive aging: effects of a dopaminergic antagonist on brain activity during working memory. Biol Psychiatry 67:575–580

    Article  PubMed  CAS  Google Scholar 

  • Green MF (2006) Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 67(Suppl 9):3–8

    PubMed  Google Scholar 

  • Gronwall DM (1977) Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 44:367–373

    Article  PubMed  CAS  Google Scholar 

  • Guo N, Hwang DR, Lo ES, Huang YY, Laruelle M, Abi-Dargham A (2003) Dopamine depletion and in vivo binding of PET D1 receptor radioligands: implications for imaging studies in schizophrenia. Neuropsychopharmacology 28:1703–1711

    Article  PubMed  CAS  Google Scholar 

  • Hall H, Sedvall G, Magnusson O, Kopp J, Halldin C, Farde L (1994) Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacology 11:245–256

    Article  PubMed  CAS  Google Scholar 

  • Hurlemann R, Matusch A, Kuhn KU, Berning J, Elmenhorst D, Winz O, Kolsch H, Zilles K, Wagner M, Maier W, Bauer A (2008) 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology (Berl) 195:579–590

    Article  CAS  Google Scholar 

  • Kegeles LS, Slifstein M, Xu X, Urban N, Thompson JL, Moadel T, Harkavy-Friedman JM, Gil R, Laruelle M, Abi-Dargham A (2010) Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18 F]fallypride positron emission tomography. Biol Psychiatry 68:634–641

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kosaka J, Takahashi H, Ito H, Takano A, Fujimura Y, Matsumoto R, Nozaki S, Yasuno F, Okubo Y, Kishimoto T, Suhara T (2010) Decreased binding of [11C]NNC112 and [11C]SCH23390 in patients with chronic schizophrenia. Life Sci 86:814–818

    Article  PubMed  CAS  Google Scholar 

  • Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D2 receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21:1034–1057

    Article  PubMed  CAS  Google Scholar 

  • McClure MM, Barch DM, Flory JD, Harvey PD, Siever LJ (2008) Context processing in schizotypal personality disorder: evidence of specificity of impairment to the schizophrenia spectrum. J Abnorm Psychol 117:342–354

    Article  PubMed  PubMed Central  Google Scholar 

  • McClure MM, Harvey PD, Goodman M, Triebwasser J, New A, Koenigsberg HW, Sprung LJ, Flory JD, Siever LJ (2010) Pergolide treatment of cognitive deficits associated with schizotypal personality disorder: continued evidence of the importance of the dopamine system in the schizophrenia spectrum. Neuropsychopharmacology 35:1356–1362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Minzenberg MJ, Xu K, Mitropoulou V, Harvey PD, Finch T, Flory JD, New AS, Goldman D, Siever LJ (2006) Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups. Psychiatr Genet 16:117–124

    Article  PubMed  Google Scholar 

  • Mitropoulou V, Harvey PD, Maldari LA, Moriarty PJ, New AS, Silverman JM, Siever LJ (2002) Neuropsychological performance in schizotypal personality disorder: evidence regarding diagnostic specificity. Biol Psychiatry 52:1175–1182

    Article  PubMed  Google Scholar 

  • Mitropoulou V, Harvey PD, Zegarelli G, New AS, Silverman JM, Siever LJ (2005) Neuropsychological performance in schizotypal personality disorder: importance of working memory. Am J Psychiatry 162:1896–1903

    Article  PubMed  Google Scholar 

  • Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M, Kegeles LS, Talbot PS, Huang Y, Hwang DR, Khenissi L, Cooper TB, Laruelle M, Abi-Dargham A (2005) Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry 162:2352–2359

    Article  PubMed  Google Scholar 

  • Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ 3rd, Gold JM, Goldberg T, Heaton RK, Keefe RS, Kraemer H, Mesholam-Gately R, Seidman LJ, Stover E, Weinberger DR, Young AS, Zalcman S, Marder SR (2008) The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry 165:203–213

    Article  PubMed  Google Scholar 

  • Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T (1994) Diagnostic Interview for Genetic Studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 51:849–859

    Article  PubMed  Google Scholar 

  • Pfohl B, Blum N, Zimmerman M (1997) Structured Interview for DSM-IV Personality: SIDP-IV. American Psychiatric Publishing, Washington, DC

    Google Scholar 

  • Poels EM, Girgis RR, Thompson JL, Slifstein M, Abi-Dargham A (2013) In vivo binding of the dopamine-1 receptor PET tracers [(11)C]NNC112 and [(11)C]SCH23390: a comparison study in individuals with schizophrenia. Psychopharmacology (Berl) 228:167–174

    Article  CAS  Google Scholar 

  • Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baare W, Svarer C, Lublin H, Knudsen GM, Glenthoj B (2010) Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry 67:9–16

    Article  PubMed  Google Scholar 

  • Rosell DR, Zaluda LC, McClure MM, Strike KS, Barch DM, Harvey PD, Girgis RR, Lieberman JA, Siever LJ (2013) Clinical testing of a D1 agonist for cognitive enhancement in the schizophrenia spectrum Society of Biological Psychiatry 68th Annual Scientific Meeting. CA, USA, San Francisco

    Google Scholar 

  • Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950

    Article  PubMed  CAS  Google Scholar 

  • Siever LJ, Davis KL (2004) The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 161:398–413

    Article  PubMed  Google Scholar 

  • Sjogren P, Thomsen AB, Olsen AK (2000) Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy. J Pain Symptom Manag 19:100–108

    Article  CAS  Google Scholar 

  • Slifstein M, Kegeles LS, Gonzales R, Frankle WG, Xu X, Laruelle M, Abi-Dargham A (2007) [11C]NNC 112 selectivity for dopamine D1 and serotonin 5-HT(2A) receptors: a PET study in healthy human subjects. J Cereb Blood Flow Metab 27:1733–1741

    Article  PubMed  CAS  Google Scholar 

  • Slifstein M, Kolachana B, Simpson EH, Tabares P, Cheng B, Duvall M, Gordon Frankle W, Weinberger DR, Laruelle M, Abi-Dargham A (2008) COMT genotype predicts cortical-limbic D1 receptor availability measured with [(11)C]NNC112 and PET. Mol Psychiatry 13:821–827

    Article  PubMed  CAS  Google Scholar 

  • Tombaugh TN (2006) A comprehensive review of the Paced Auditory Serial Addition Test (PASAT). Arch Clin Neuropsychol 21:53–76

    Article  PubMed  Google Scholar 

  • Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF (2005) Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology 30:1861–1869

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the research participants of this study and express gratitude for the expert assistance of Rawad Ayoub, Jennifer Bae, Felipe Castillo, John Castrillon, Elizabeth Hackett, Elisabeth Iskander, Olga Kambalov, and Ethan Rothstein. This work was supported by a Merit Review grant (7609-028) from the US Department of Veterans Affairs to Larry J. Siever, by grant MH56140 from the National Institute of Mental Health to Larry J. Siever, and by the Veterans Affairs VISN 3 Mental Illness Research, Education and Clinical Center (MIRECC).

Conflict of interest

The authors declare no conflicts of interest; however, the following coauthors have appointments at the James J. Peters Veterans Affairs Medical Center, Bronx, NY (in addition to the Mount Sinai School of Medicine, New York, NY): Daniel R. Rosell, Yosefa Ehrlich, Erin A. Hazlett, and Larry J. Siever. In addition, some coauthors have financial relationships with pharmaceutical companies. Specifically, Mark Slifstein serves as a consultant for Amgen and receives research support from Pierre Fabre; Ragy R. Girgis receives research support from Otsuka; Lawrence S. Kegeles receives research support from Pfizer and Amgen; and Anissa Abi-Dargham is a consultant for Amgen and Roche, and receives research support from Otsuka, Takeda, Forest, and Pierre Fabre.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    Judy L. Thompson, Mark Slifstein, Ragy R. Girgis, Xiaoyan Xu, Lawrence S. Kegeles & Anissa Abi-Dargham

  2. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Daniel R. Rosell, Yosefa Ehrlich, Erin A. Hazlett & Larry J. Siever

  3. James J. Peters Veterans Affairs Medical Center, Bronx, NY, 10468, USA

    Daniel R. Rosell, Yosefa Ehrlich, Erin A. Hazlett & Larry J. Siever

  4. Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    Lawrence S. Kegeles & Anissa Abi-Dargham

  5. School of Health Related Professions, Rutgers, The State University of New Jersey, 1776 Raritan Road, Scotch Plains, NJ, 07076, USA

    Judy L. Thompson

Authors
  1. Judy L. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel R. Rosell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark Slifstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ragy R. Girgis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoyan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yosefa Ehrlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lawrence S. Kegeles
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Erin A. Hazlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anissa Abi-Dargham
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Larry J. Siever
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Judy L. Thompson.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 581 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thompson, J.L., Rosell, D.R., Slifstein, M. et al. Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [11C]NNC112. Psychopharmacology 231, 4231–4240 (2014). https://doi.org/10.1007/s00213-014-3566-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3566-6

Keywords

Search

Navigation