DOPAMINE TRANSPORTER-HUMAN &MOUSE GENES, DOPAMINERGIC DISORDERS &KNOCKO

Uhl, George Richard

Abstract

The rewarding/reinforcing effects of cocaine have been thought to be produced, at least in part, by blocking reuptake of dopamine by the dopamine transporter (DAT). This is the site that accumulates each of the dopamine selective toxins that produce the best current experimental models for Parkinson's disease. The DAT gene is expressed in dopaminergic neurons of the ventral midbrain, and serves as the only currently-available marker expressed almost exclusively by these cells. During this FY, we completed sequencing of the human DAT gene, characterized each of the polymorphisms in its coding and several intronic regions, and examined the distributions of these polymorphisms in populations with drug abuse, ADHD, Tourette's syndrome, and several other phenotypes. We also completed mapping the patterns of linkage disequilibrium accross this locus. No clear coding region disease-related protein variant was identified. However, continued strengthening of association between the 3' untranslated region VNTR marker and ADHD in several studies spurs interest in regulatory region polymorphisms at this interesting locus.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Drug Abuse (NIDA)
• Type: Intramural Research (Z01)
• Project #: 1Z01DA000160-04
• Application #: 6103870
• Study Section: Special Emphasis Panel (MNB)
• Support Year: 4
• Fiscal Year: 1998

Institution

• Name: National Institute on Drug Abuse
• Country: United States

Publications

Yamashita, Motoyasu; Fukushima, Setsu; Shen, Hao-wei et al. (2006) Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology 31:2132-9

Drgon, Tomas; Lin, Zhicheng; Wang, Gene-Jack et al. (2006) Common human 5' dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol 26:875-89

Lin, Zhicheng; Walther, Donna; Yu, Xiao-Ying et al. (2005) SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism. Hum Mol Genet 14:1393-404

Radzius, Aleksandras; Gallo, Joseph; Gorelick, David et al. (2004) Nicotine dependence criteria of the DIS and DSM-III-R: a factor analysis. Nicotine Tob Res 6:303-8

Liu, Qing-Rong; Zhang, Ping-Wu; Lin, Zhicheng et al. (2004) GBPI, a novel gastrointestinal- and brain-specific PP1-inhibitory protein, is activated by PKC and inactivated by PKA. Biochem J 377:171-81

Uhl, George R (2004) Molecular genetic underpinnings of human substance abuse vulnerability: likely contributions to understanding addiction as a mnemonic process. Neuropharmacology 47 Suppl 1:140-7

Lin, Zhicheng; Zhang, Ping-Wu; Zhu, Xuguang et al. (2003) Phosphatidylinositol 3-kinase, protein kinase C, and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites. J Biol Chem 278:20162-70

Uhl, George R (2003) Dopamine transporter: basic science and human variation of a key molecule for dopaminergic function, locomotion, and parkinsonism. Mov Disord 18 Suppl 7:S71-80

Uhl, George R; Lin, Zhicheng (2003) The top 20 dopamine transporter mutants: structure-function relationships and cocaine actions. Eur J Pharmacol 479:71-82

Hall, F Scott; Sora, I; Uhl, G R (2003) Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice. Neuropsychopharmacology 28:620-8