Parkinson's disease (PD) is a progressive disease related to degeneration of nigrostriatal dopaminergic neurons and can be caused by genetic and environmental factors. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can produce Parkinsonian syndrome (Langston et al. 1983) and is an Received February 28, 2010; revised manuscript received April 26, 2010; accepted April 26, 2010. Address correspondence and reprint requests to Kai-Yuan Tzen, MD, Department of Nuclear Medicine, National Taiwan University Hospital, No.7 Chung Shan South Road, Taipei 100, Taiwan. E-mail: tzenky@ntuh.gov.tw or Chun-Jung Lin, School of Pharmacy, College of Medicine, National Taiwan University,1 Jen-Ai Road, Section 1, Taipei, Taiwan 100. E-mail: clementumich@ntu.edu.tw Abbreviations used: 3-MT, 3-methoxytyramine; ARBECs, adult rat brain endothelial cells; AUC, area under the time-concentration curve; BB, blood-brain barrier; BMECs, brain microvessel endothelial cells; BSA, bovine serum albumin; DC, detergent compatible; DOPAC, 3,4-dihydroxyphenylacetic acid; ECF, extracellular fluid; FDOPA, 6-[ AbstractThe cellular localization of organic cation transporter (OCT) 1 and OCT2 in isolated brain microvessel endothelial cells from humans, rats, and mice and in cultured adult rat brain endothelial cells was examined by confocal microscopy and in isolated luminal and abluminal membrane fractions by Western blot analysis. Cellular uptake of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was measured with or without OCT1/OCT2 silencing. The interaction between MPTP and amantadine was studied by in vitro kinetic analysis and in vivo brain microdialysis. MPTP-induced dopaminergic toxicity was examined by measuring dopamine levels in the brain striatum and by positron emission tomography scanning. The results showed that both OCT1 and OCT2 were mainly expressed on the luminal side of brain microvessel endothelial cells and adult rat brain endothelial cells. Cellular uptake of MPTP was significantly (p < 0.05) decreased by about 53%, 60%, or 91% following silencing of OCT1, OCT2, or both, respectively. Amantadine competitively inhibited MPTP uptake in vitro and significantly (p < 0.05) reduced the area under the time-concentration curve for MPTP and MPP + in the brain extracellular fluid in rats and mice by 65-70% and 35-85%, respectively. MPTP-induced dopaminergic toxicity in mice was ameliorated by amantadine without stimulating dopamine turnover. In conclusion, OCT1 and OCT2 are important for MPTP transfer across the blood-brain barrier and amantadine reduces the blood-brain barrier transfer of MPTP and MPTP-induced dopaminergic toxicity in rodents.

The results suggest that ADHD could be heritable via abnormal DAT activities.

Background. It is well-known that attention deficit hyperactivity disorder (ADHD) is associated with changes in the dopaminergic system. However, the relationship between central dopaminergic tone and the blood oxygen level-dependent (BOLD) signal during receipt of rewards and penalties in the corticostriatal pathway in adults with ADHD is unclear. Methods. Single-photon emission computed tomography with [99mTC]TRODAT-1 was used to assess striatal dopamine transporter (DAT) availability. Event-related functional magnetic resonance imaging was conducted on subjects performing the Iowa Gambling Test. Result. DAT availability was found to be associated with the BOLD response, which was a covariate of monetary loss, in the medial prefrontal cortex (r = 0.55, P = .03), right ventral striatum (r = 0.69, P = .003), and right orbital frontal cortex (r = 0.53, P = .03) in adults with ADHD. However, a similar correlation was not found in the controls. Conclusions. The results confirmed that dopaminergic tone may play a different role in the penalty-elicited response of adults with ADHD. It is plausible that a lower neuro-threshold accompanied by insensitivity to punishment could be exacerbated by the hypodopaminergic tone in ADHD.

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