Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: A positron emission tomography study in healthy subjects

• Published in: NeuroImage Vol. 40; no. 3; pp. 1222 - 1231
• Main Authors: Vernaleken, Ingo, Kumakura, Yoshitaka, Buchholz, Hans-Georg, Siessmeier, Thomas, Hilgers, Ralf-Dieter, Bartenstein, Peter, Cumming, Paul, Gründer, Gerhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2008; Elsevier BV; Elsevier Limited
• Subjects: [18F]-Fluoro-l-DOPA; Adult; Algorithms; Antipsychotic treatment; Brain; Brain - diagnostic imaging; Brain Chemistry; Brain Chemistry - drug effects; Cognition; Cognition - physiology; Data Interpretation, Statistical; Dopamine; Dopamine - metabolism; Dopamine Antagonists; Dopamine Antagonists - adverse effects; Dopamine Antagonists - pharmacology; Dopamine D2 Receptor Antagonists; Female; Fluorodeoxyglucose F18; Fluorodeoxyglucose F18 - pharmacokinetics; Haloperidol; Haloperidol - adverse effects; Haloperidol - pharmacology; Humans; Image Processing, Computer-Assisted; Kinetics; Male; Mental disorders; Metabolites; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Psychomotor Performance; Psychomotor Performance - drug effects; Radiopharmaceuticals; Radiopharmaceuticals - pharmacokinetics; Receptors, Dopamine D3; Receptors, Dopamine D3 - antagonists & inhibitors; Striatum; Values; Striatum; Cognition; Dopamine; Antipsychotic treatment; [18F]-Fluoro-l-DOPA
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2007.12.045

The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D2/3-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-[18F]-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 [18F]fluorodopamine formed in brain (kloss) and the storage for FDOPA and its brain metabolites (Vd). 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 [18F]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 [18F]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 D1-receptor mediated transmission during D2 blockade.