title: Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: A positron emission tomography study in healthy subjects.
abstract: The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D(2/3)-receptor antagonism and dopamine transmission is not described in healthy subjects. We therefore tested effects of acute haloperidol (5 mg/d over 3 days) on continuous performance task (CPT) performance and 6-[(18)F]-fluoro-l-DOPA (FDOPA) PET parameters. Nine physically and mentally healthy male men performed two FDOPA-PET scans including arterial plasma withdrawal. Over 3 days before the second scan, all subjects were treated with 5 mg/d haloperidol orally. Using our novel steady-state analysis, we calculated the intrinsic rate of the cerebral FDOPA utilization (K), the turnover of [(18)F]fluorodopamine formed in brain (k(loss)) and the storage for FDOPA and its brain metabolites (V(d)). Furthermore, a ds-CPT and EPS-screening was performed before every PET scan. We found that FDOPA kinetics in those normal subjects with relatively high baseline K showed a more pronounced sensitivity to haloperidol treatment, manifesting in reduced storage capacity and elevated turnover of [(18)F]fluorodopamine, whereas subjects with lower K showed the opposite pattern of responses. Furthermore, low baseline K predicted improvements in the CPT task after haloperidol, whereas participants with higher baseline K showed a decline in cognitive performance. We conclude that the initial increase of [(18)F]fluorodopamine turnover after acute haloperidol challenge is associated with an over-stimulation in individuals with initially more pharmacologically responsive dopamine systems, but optimizes cognitive performance in those with lower normal FDOPA utilization at baseline. We hypothesize that these effects may be driven by D(1)-receptor mediated transmission during D(2) blockade.
authors.affiliation: Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. ivernaleken@ukaachen.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Vernaleken
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kumakura
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Buchholz
authors.forename: Thomas
authors.initials: T
authors.lastname: Siessmeier
authors.forename: Ralf-Dieter
authors.initials: RD
authors.lastname: Hilgers
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
mesh_terms: D000328:Adult; D000465:Algorithms; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry / Q000187:drug effects; D003071:Cognition / Q000502:physiology*; D003627:Data Interpretation, Statistical; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011597:Psychomotor Performance / Q000187:drug effects*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D019275:Radiopharmaceuticals; D050637:Receptors, Dopamine D3; D019788:Fluorodeoxyglucose F18; D006220:Haloperidol; D004298:Dopamine