Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers.

BACKGROUND: There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. METHODS: We obtained baseline 6-[(18)F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (kloss); and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. RESULTS: Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. CONCLUSIONS: The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments.

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

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.

Neuropsychological correlates of transcription factor AP-2Beta, and its interaction with COMT and MAOA in healthy females.

BACKGROUND: The transcription factor AP-2ß has been shown to impact clinical and neuropsychological properties. Apparently, it regulates the transcription of genes that code for molecules which are part of the catecholaminergic transmission system. This investigation focuses on possible effects of the transcription factor AP-2ß intron 2 polymorphism on cognitive performance parameters. METHODS: This hypothesis-driven investigation examined the effects and interactions of the transcription factor AP-2ß intron 2 polymorphism, the Val158Met catechol-O-methyltransferase (COMT) polymorphism, and the variable number of tandem repeat polymorphism of monoamine oxidase A (MAOA) on cognitive performance parameters within a group of 200 healthy women (age: mean ± SD, 23.93 ± 3.33 years). RESULTS: The AP-2ß polymorphism significantly influenced cognitive performance (in particular, the Trail Making Test part B), whereas the MAOA and COMT polymorphisms did not. However, there was an interaction effect of the AP-2ß × MAOA × COMT genotypes on the decision bias ß of the degraded-stimulus version of the continuous performance task. Only the Val158Met COMT polymorphism showed an influence on personality questionnaires (openness and self-transcendence; NEO Five-Factor Inventory, Temperament and Character Inventory). CONCLUSION: The transcription factor AP-2ß intron 2 polymorphism had more influence on cognition than the MAOA and COMT polymorphisms. Possibly, the AP-2ß genotype might influence cognition through pathways other than those that regulate MAOA and COMT transcription. Interactions of transcription factor AP-2ß, COMT, and MAOA polymorphisms suggest higher leverage effects of transcription factor AP-2ß in subjects with high dopamine availability.