Striatal and Extrastriatal Dopamine Transporter Availability in Schizophrenia and Its Clinical Correlates: A Voxel-Based and High-Resolution PET Study

Neuroimaging studies investigating dopamine (DA) function widely support the hypothesis of presynaptic striatal DA hyperactivity in schizophrenia. However, published data on the striatal DA transporter (DAT) appear less consistent with this hypothesis, probably partly due to methodological limitations. Moreover, DAT in extrastriatal regions has been very poorly investigated in the context of schizophrenia. In order to address these issues, we used a high resolution positron emission tomograph and the selective DAT radioligand [11C]PE2I, coupled with a whole brain voxel-based analysis method to investigate DAT availability in striatal but also extra-striatal regions in 21 male chronic schizophrenia patients compared to 30 healthy male controls matched by age. We found higher DAT availability in schizophrenia patients in midbrain, striatal, and limbic regions. DAT availability in amygdala/hippocampus and putamen/pallidum was positively correlated with hallucinations and suspiciousness/persecution, respectively. These results are consistent with an increase of presynaptic DA function in patients with schizophrenia, and support the involvement of both striatal and extrastriatal DA dysfunction in positive psychotic symptoms. The study also highlights the whole brain voxel-based analysis method to explore DA dysfunction in schizophrenia.

[1]  J. Martinot,et al.  Dopamine Transporter Correlates and Occupancy by Modafinil in Cocaine-Dependent Patients: A Controlled Study With High-Resolution PET and [11C]-PE2I , 2016, Neuropsychopharmacology.

[2]  A. Falini,et al.  Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia , 2015, European Psychiatry.

[3]  Hui-Feng Duan,et al.  A longitudinal study on intrinsic connectivity of hippocampus associated with positive symptom in first-episode schizophrenia , 2015, Behavioural Brain Research.

[4]  Hanzhang Lu,et al.  Amygdala Hyperactivity at Rest in Paranoid Individuals With Schizophrenia. , 2015, The American journal of psychiatry.

[5]  Adrian Preda,et al.  Visual hallucinations are associated with hyperconnectivity between the amygdala and visual cortex in people with a diagnosis of schizophrenia. , 2015, Schizophrenia bulletin.

[6]  Michael W. Cole,et al.  Amygdala connectivity differs among chronic, early course, and individuals at risk for developing schizophrenia. , 2014, Schizophrenia bulletin.

[7]  T. Boraud,et al.  The Michelin red guide of the brain: role of dopamine in goal-oriented navigation , 2014, Front. Syst. Neurosci..

[8]  Federico Turkheimer,et al.  Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. , 2013, Brain : a journal of neurology.

[9]  B. Bogerts,et al.  Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia. , 2013, Brain : a journal of neurology.

[10]  A. Meyer-Lindenberg,et al.  Striatal presynaptic dopamine in schizophrenia, Part I: meta-analysis of dopamine active transporter (DAT) density. , 2013, Schizophrenia bulletin.

[11]  A. Meyer-Lindenberg,et al.  Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies. , 2013, Schizophrenia bulletin.

[12]  Claude Comtat,et al.  Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high‐resolution PET study , 2012, Addiction biology.

[13]  Mark Slifstein,et al.  The nature of dopamine dysfunction in schizophrenia and what this means for treatment. , 2012, Archives of general psychiatry.

[14]  T Warbrick,et al.  Hippocampal subfields predict positive symptoms in schizophrenia: First evidence from brain morphometry , 2012, Translational Psychiatry.

[15]  Christer Halldin,et al.  Quantitative PET analyses of regional [11C]PE2I binding to the dopamine transporter — Application to juvenile myoclonic epilepsy , 2012, NeuroImage.

[16]  J. Lieberman,et al.  Presynaptic regulation of dopamine transmission in schizophrenia. , 2011, Schizophrenia bulletin.

[17]  J. Goldstein,et al.  Sex differences in schizophrenia , 2010, International review of psychiatry.

[18]  I. Kanno,et al.  Quantitative analysis of dopamine transporters in human brain using [11C]PE2I and positron emission tomography: evaluation of reference tissue models , 2010, Annals of nuclear medicine.

[19]  Angus W. MacDonald,et al.  The functional neuroanatomy of symptom dimensions in schizophrenia: A qualitative and quantitative review of a persistent question , 2010, Neuroscience & Biobehavioral Reviews.

[20]  Harumasa Takano,et al.  Increase in thalamic binding of [(11)C]PE2I in patients with schizophrenia: a positron emission tomography study of dopamine transporter. , 2009, Journal of psychiatric research.

[21]  Christine DeLorenzo,et al.  Modeling Considerations for In Vivo Quantification of the Dopamine Transporter using [11C]PE2I and Positron Emission Tomography , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  Andrew J. Reader,et al.  Impact of Image-Space Resolution Modeling for Studies with the High-Resolution Research Tomograph , 2008, Journal of Nuclear Medicine.

[23]  H. Möller,et al.  Dual-isotope SPECT imaging of striatal dopamine: First episode, drug naïve schizophrenic patients , 2008, Schizophrenia Research.

[24]  Harumasa Takano,et al.  Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography , 2008, NeuroImage.

[25]  Christer Halldin,et al.  Measurement of Striatal and Extrastriatal Dopamine Transporter Binding with High-Resolution PET and [11C]PE2I: Quantitative Modeling and Test—Retest Reproducibility , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  Po See Chen,et al.  Decreased dopamine transporter availability in male smokers — A dual isotope SPECT study , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[27]  Caryn Lerman,et al.  Dopamine Transporter Binding in Smokers and Nonsmokers , 2007, Clinical nuclear medicine.

[28]  Claude Comtat,et al.  Assessment of 11C-PE2I Binding to the Neuronal Dopamine Transporter in Humans with the High-Spatial-Resolution PET Scanner HRRT , 2007, Journal of Nuclear Medicine.

[29]  Ronald Boellaard,et al.  Performance evaluation of the ECAT HRRT: an LSO-LYSO double layer high resolution, high sensitivity scanner , 2007, Physics in medicine and biology.

[30]  J. Seidel,et al.  Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[31]  E. Fernandez-Egea,et al.  Lower striatal dopamine transporter binding in neuroleptic-naive schizophrenic patients is not related to antipsychotic treatment but it suggests an illness trait , 2007, Psychopharmacology.

[32]  Christer Halldin,et al.  Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study , 2006, European Journal of Nuclear Medicine and Molecular Imaging.

[33]  J. Leon,et al.  A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors , 2005, Schizophrenia Research.

[34]  M. Bannon.  The dopamine transporter: role in neurotoxicity and human disease. , 2005, Toxicology and applied pharmacology.

[35]  L. Siever,et al.  Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide , 2004, Biological Psychiatry.

[36]  J. Sundsfjord,et al.  123I-β-CIT SPECT demonstrates increased presynaptic dopamine transporter binding sites in basal ganglia in vivo in schizophrenia , 2004, Psychopharmacology.

[37]  Yuan-Hwa Chou,et al.  [11C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[38]  S. Kapur.  Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. , 2003, The American journal of psychiatry.

[39]  J. Hietala,et al.  Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects , 2002, Biological Psychiatry.

[40]  R. Gur,et al.  Striatal dopamine transporters and cognitive functioning in healthy men and women. , 2001, The American journal of psychiatry.

[41]  D. Linszen,et al.  Dopamine transporter density in young patients with schizophrenia assessed with [123]FP-CIT SPECT , 2001, Schizophrenia Research.

[42]  C. Crouzel,et al.  Highly efficient synthesis of [11C]PE2I, a selective radioligand for the quantification of the dopamine transporter using PET , 2000 .

[43]  F. Tarazi,et al.  Olanzapine, quetiapine, and risperidone: long-term effects on monoamine transporters in rat forebrain , 2000, Neuroscience Letters.

[44]  L. Reneman,et al.  Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers , 2000, European Journal of Nuclear Medicine.

[45]  J. Krystal,et al.  Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]β-CIT , 2000, Biological Psychiatry.

[46]  L. Reneman,et al.  [123I]FP-CIT binding in rat brain after acute and sub-chronic administration of dopaminergic medication , 2000, European Journal of Nuclear Medicine.

[47]  Ralph Myers,et al.  Assessment of Spatial Normalization of PET Ligand Images Using Ligand-Specific Templates , 1999, NeuroImage.

[48]  R. Blakely,et al.  Pharmacological profile of neuroleptics at human monoamine transporters. , 1999, European journal of pharmacology.

[49]  D. Guilloteau,et al.  Visualization of the Dopamine Transporter in the Human Brain Postmortem with the New Selective Ligand [125I]PE2I , 1999, NeuroImage.

[50]  Vincent J. Cunningham,et al.  Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model , 1997, NeuroImage.

[51]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[52]  F. Carroll,et al.  Characterization and localization of [125I]RTI-121 binding sites in human striatum and medial temporal lobe. , 1995, The Journal of pharmacology and experimental therapeutics.

[53]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[54]  Jeffrey A. Lieberman,et al.  Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia , 1993, Biological Psychiatry.

[55]  K. Davis,et al.  Dopamine in schizophrenia: a review and reconceptualization. , 1991, The American journal of psychiatry.

[56]  L. Kozlowski,et al.  Nicotine addiction and its assessment. , 1990, Ear, nose, & throat journal.

[57]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[58]  B. Berger,et al.  Morphological evidence for a dopaminergic terminal field in the hippocampal formation of young and adult rat , 1985, Neuroscience.

[59]  B. Bogerts,et al.  A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics. , 1983, Biological psychiatry.

[60]  Herve Simon,et al.  Origin of dopaminergic innervation of the rat hippocampal formation , 1980, Neuroscience Letters.