title: Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated by Reboxetine and Amisulpride in Healthy Subjects.
abstract: BACKGROUND
  Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations.
  
  
  METHODS
  Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4 mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC).
  
  
  RESULTS
  fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen.
  
  
  CONCLUSIONS
  Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric populations.
authors.affiliation: Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany (Drs Metzger and Walter); Department of Psychiatry, University of Ulm, Germany (Drs Wiegers, Abler, and Graf); Leibniz Institute for Neurobiology, Magdeburg, Germany (Drs Metzger and Walter); Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany (Dr Metzger); German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany (Dr Metzger). coraline.metzger@med.ovgu.de.
authors.forename: Coraline D
authors.initials: CD
authors.lastname: Metzger
authors.affiliation: Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany (Drs Metzger and Walter); Department of Psychiatry, University of Ulm, Germany (Drs Wiegers, Abler, and Graf); Leibniz Institute for Neurobiology, Magdeburg, Germany (Drs Metzger and Walter); Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany (Dr Metzger); German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany (Dr Metzger).
authors.forename: Maike
authors.initials: M
authors.lastname: Wiegers
authors.affiliation: Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany (Drs Metzger and Walter); Department of Psychiatry, University of Ulm, Germany (Drs Wiegers, Abler, and Graf); Leibniz Institute for Neurobiology, Magdeburg, Germany (Drs Metzger and Walter); Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany (Dr Metzger); German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany (Dr Metzger).
authors.forename: Martin
authors.initials: M
authors.lastname: Walter
authors.affiliation: Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany (Drs Metzger and Walter); Department of Psychiatry, University of Ulm, Germany (Drs Wiegers, Abler, and Graf); Leibniz Institute for Neurobiology, Magdeburg, Germany (Drs Metzger and Walter); Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany (Dr Metzger); German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany (Dr Metzger).
authors.forename: Birgit
authors.initials: B
authors.lastname: Abler
authors.affiliation: Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany (Drs Metzger and Walter); Department of Psychiatry, University of Ulm, Germany (Drs Wiegers, Abler, and Graf); Leibniz Institute for Neurobiology, Magdeburg, Germany (Drs Metzger and Walter); Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany (Dr Metzger); German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany (Dr Metzger).
authors.forename: Heiko
authors.initials: H
authors.lastname: Graf
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000328:Adult; D000077582:Amisulpride; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D018492:Dopamine Antagonists / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D000077593:Reboxetine; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018492:Dopamine Antagonists; D009025:Morpholines; D013469:Sulpiride; D000077582:Amisulpride; D000077593:Reboxetine
keywords: Amisulpride; dopamine; noradrenaline; pharmacological resting state fMRI; reboxetine