title: Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study.
abstract: OBJECTIVE
  Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11-labeled FLB457 in combination with the amphetamine paradigm was clearly established.
  
  
  OBJECTIVE
  To (1) test amphetamine-induced dopamine release in the dorsolateral PFC (DLPFC) in drug-free or drug-naive patients with schizophrenia (SCZ) and healthy control (HC) individuals matched for age, sex, race/ethnicity, and familial socioeconomic status;(2) test blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging activation during a working memory task in the same participants; and (3) examine the relationship between positron emission tomographic and functional magnetic resonance imaging outcome measures.
  
  
  METHODS
  Positron emission tomographic imaging with carbon 11-labeled FLB457 before and following 0.5 mg/kg of amphetamine by mouth. Blood oxygenation level-dependent functional magnetic resonance imaging during the self-ordered working memory task. Twenty patients with schizophrenia recruited from the inpatient and outpatient research facilities at New York State Psychiatric Institute and 21 healthy control individuals participated, and data were acquired between June 16, 2011, and February 25, 2014.
  
  
  METHODS
  The percentage change in binding potential (∆BPND) in the DLPFC following amphetamine, BOLD activation during the self-ordered working memory task compared with the control task, and the correlation between these 2 outcome measures.
  
  
  RESULTS
  We observed significant differences in the effect of amphetamine on DLPFC BPND (mean [SD], ∆BPND in HC: -7.5% [11%]; SCZ: +1.8% [11%]; P = .01); a generalized blunting in dopamine release in SCZ involving most extrastriatal regions and the midbrain; and a significant association between ∆BPND and BOLD activation in the DLPFC in the overall sample including patients with SCZ and HC individuals.
  
  
  CONCLUSIONS
  To our knowledge, these results provide the first in vivo evidence for a deficit in the capacity for dopamine release in the DLPFC in SCZ and suggest a more widespread deficit extending to many cortical and extrastriatal regions including the midbrain. This contrasts with the well-replicated excess in dopamine release in the associative striatum in SCZ and suggests a differential regulation of striatal dopamine release in associative striatum vs extrastriatal regions. Furthermore, dopamine release in the DLPFC relates to working memory-related activation of this region, suggesting that blunted release may affect frontal cortical function.
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Mark
authors: M
authors: Slifstein
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Elsmarieke
authors: E
authors: van de Giessen
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Jared
authors: J
authors: Van Snellenberg
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York3The State University of New Jersey, Rutgers.
authors: Judy L
authors: JL
authors: Thompson
authors: Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors: Rajesh
authors: R
authors: Narendran
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Roberto
authors: R
authors: Gil
authors: New York State Psychiatric Institute, New York.
authors: Elizabeth
authors: E
authors: Hackett
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Ragy
authors: R
authors: Girgis
authors: New York State Psychiatric Institute, New York.
authors: Najate
authors: N
authors: Ojeil
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Holly
authors: H
authors: Moore
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors: Deepak
authors: D
authors: D'Souza
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors: Robert T
authors: RT
authors: Malison
authors: PET Center, Yale University School of Medicine, New Haven, Connecticut7Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut.
authors: Yiyun
authors: Y
authors: Huang
authors: PET Center, Yale University School of Medicine, New Haven, Connecticut7Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut.
authors: Keunpoong
authors: K
authors: Lim
authors: PET Center, Yale University School of Medicine, New Haven, Connecticut7Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut.
authors: Nabeel
authors: N
authors: Nabulsi
authors: PET Center, Yale University School of Medicine, New Haven, Connecticut7Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut.
authors: Richard E
authors: RE
authors: Carson
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York.
authors: Jeffrey A
authors: JA
authors: Lieberman
authors: Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York8Department of Radiology, Columbia University, New York, New York.
authors: Anissa
authors: A
authors: Abi-Dargham
mesh_terms: D000328:Adult; D000661:Amphetamine / Q000494:pharmacology; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D008636:Mesencephalon / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011759:Pyrrolidines; D012457:Salicylamides; D012559:Schizophrenia / Q000378:metabolism*; D012565:Schizophrenic Psychology; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D011759:Pyrrolidines; D012457:Salicylamides; C065065:FLB 457; D000661:Amphetamine; D004298:Dopamine
references: Biol Psychiatry. 2010 Oct 1;68(7):634-41
references: 20673873
references: Nature. 1997 Feb 13;385(6617):634-6
references: 9024661
references: Q J Nucl Med. 1998 Sep;42(3):211-21
references: 9796369
references: Mol Psychiatry. 2014 Mar;19(3):302-10
references: 23439486
references: Science. 1991 Feb 22;251(4996):947-50
references: 1825731
references: J Cereb Blood Flow Metab. 2007 Sep;27(9):1533-9
references: 17519979
references: Brain Res. 2002 May 17;936(1-2):58-67
references: 11988230
references: Synapse. 2011 Oct;65(10):991-7
references: 21360596
references: J Neurosci. 1991 Jul;11(7):1907-17
references: 2066768
references: Nucl Med Biol. 2001 Jul;28(5):595-608
references: 11516703
references: Brain Res. 1993 Apr 23;609(1-2):237-43
references: 8099521
references: Psychopharmacology (Berl). 1994 Oct;116(2):143-51
references: 7862943
references: J Neurosci. 2002 May 1;22(9):3708-19
references: 11978847
references: Clin Neuropharmacol. 1992;15 Suppl 1 Pt A:568A-569A
references: 1498953
references: Hum Brain Mapp. 2005 May;25(1):60-9
references: 15846819
references: J Pharmacol Exp Ther. 1997 Oct;283(1):183-9
references: 9336323
references: J Neurosci. 2004 Feb 11;24(6):1446-50
references: 14960617
references: Am J Psychiatry. 1996 Mar;153(3):321-30
references: 8610818
references: Biol Psychiatry. 2000 Mar 1;47(5):361-70
references: 10704948
references: Neuropsychopharmacology. 2002 Nov;27(5):699-711
references: 12431845
references: J Neurosci. 2014 Apr 16;34(16):5575-82
references: 24741047
references: J Neurophysiol. 2014 Jun 1;111(11):2161-3
references: 24401705
references: Arch Gen Psychiatry. 1998 Apr;55(4):362-8
references: 9554432
references: Am J Psychiatry. 1999 Oct;156(10):1580-9
references: 10518170
references: Int Rev Neurobiol. 2007;78:1-39
references: 17349856
references: J Cereb Blood Flow Metab. 2000 Feb;20(2):225-43
references: 10698059
references: Brain. 2013 Nov;136(Pt 11):3242-51
references: 24097339
references: Curr Psychiatry Rep. 2007 Aug;9(4):329-36
references: 17880866
references: Eur J Neurosci. 1997 Oct;9(10):2077-85
references: 9421168
references: Hum Brain Mapp. 1994;1(4):293-304
references: 24591198
references: Trends Cogn Sci. 2012 Jan;16(1):27-34
references: 22169777
references: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16366-71
references: 20805489
references: Science. 2000 Mar 17;287(5460):2020-2
references: 10720329
references: Synapse. 2011 Jan;65(1):35-40
references: 20506186
references: Synapse. 2009 Jun;63(6):447-61
references: 19217025
references: Schizophr Res. 2005 Sep 1;77(1):43-58
references: 16005384
references: J Neurochem. 1993 Feb;60(2):527-35
references: 8419534
references: Arch Gen Psychiatry. 2009 Aug;66(8):811-22
references: 19652121
references: J Psychopharmacol. 1999 Dec;13(4):358-71
references: 10667612
references: Synapse. 1999 May;32(2):93-109
references: 10231129
references: J Psychopharmacol. 2012 Jun;26(6):794-805
references: 21768159
references: J Neurophysiol. 1994 Feb;71(2):515-28
references: 7909839
references: Prog Mol Biol Transl Sci. 2014;122:211-31
references: 24484703
references: Arch Gen Psychiatry. 1994 Nov;51(11):849-59; discussion 863-4
references: 7944874
references: J Neurochem. 1998 Jul;71(1):274-80
references: 9648875
references: CNS Neurosci Ther. 2011 Apr;17(2):104-9
references: 21199451
references: Arch Gen Psychiatry. 2012 Aug;69(8):776-86
references: 22474070
references: Adv Pharmacol. 1998;42:133-6
references: 9327864
references: Schizophr Bull. 1987;13(2):261-76
references: 3616518