Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study

Abstract

Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.

Keywords: [18F]FDOPA PET; cognition; dopamine turnover; long-term effects; methylphenidate; stimulants.

Figure 1.

a, Reductions in [¹⁸F]FDOPA k_loss in bilateral putamen after MPH challenge (p = 0.007, n = 19, complete sample). b, Correlation between time at Trail Making Test B and no drug [¹⁸F]FDOPA K in left putamen (p = 0.029, n = 14, conventional order group). c, Correlation between no drug [¹⁸F]FDOPA K and concentration performance parameter (CP) in right and left putamen (PUT) (right: p = 0.039, n = 12; left p = 0.007, n = 13, conventional order group). d, Correlation between change in [¹⁸F]FDOPA k_loss and change in concentration performance under MPH (p = 0.040, n = 12, conventional order group).