Human and mouse dopamine transporter genes: conservation of 5′-flanking sequence elements and gene structures

Donovan, David M.; Vandenbergh, David J.; Perry, M. P.; Bird, Gary S.; Ingersoll, Roxann; Nanthakumar, Elizabeth; Uhl, George R.

doi:10.1016/0169-328x(95)00018-n

Cited by 68 publications

(34 citation statements)

References 39 publications

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“…Limited information on intronic sequences was available from the papers reporting the genomic organization of the DAT1 gene 13,27 and DNA sequence databases. Because we wanted to include all exon-intron junctions in our mutation screening, we needed to determine exon-flanking intronic sequences for introns 1 (3Ј), 3 (3Ј), 5 (3Ј), 6 (3Ј), 9 (3Ј), 12 (3Ј), 13 (5Ј and 3Ј), and 14 (5Ј and 3Ј) for selection of primers.…”

Section: Characterization Of Exon-flanking Intronic Sequencesmentioning

confidence: 99%

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1)

et al. 2000

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The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3Ј-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon-intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients' families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder. Molecular Psychiatry (2000) 5, 275-282.

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Section: Characterization Of Exon-flanking Intronic Sequencesmentioning

confidence: 99%

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1)

et al. 2000

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“…gov This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains.…”

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confidence: 99%

Cocaine, reward, movement and monoamine transporters

Uhl

Hall²,

Sora³

2002

Mol Psychiatry

189

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Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities. Cocaine is a prototypical psychomotor stimulant that increases locomotor activity and elevates mood with rewarding euphoria. 1 It also produces fearful and jittery aversive effects in many who take it. 2,3 Cocaine blocks monoamine uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET), and can also block ligand-and voltage-gated channels with somewhat lower potencies. 4 Understanding the relationships between cocaine's molecular actions and its psychomotor stimulant and aversive properties has remained surprisingly incomplete. This review focuses on recent advances in our understanding of the complex relationships between cocaine's molecular actions and its locomotor stimulant, rewarding and aversive properties.The 'DAT-is-it' hypothesis drove thinking about cocaine reward for at least a decade, ideas widely linked to Kuhar, Spealman and their colleagues 4-8 who gathered evidence from structure-activity relationships of transporter-blocking compounds with differential potencies at DAT, SERT and NET. They examined relationships between potencies of these compounds in tests of reward and binding affinities at each of the monoamine transporters. They each identified the best correlations for the rewarding effects of cocaine with DAT blockade. These authors also cited prior work from lesion studies 9-12 and electrical brain stimulation studies 13-17 that implicated dopamine pathways in Correspondence: GR Uhl, MD, PhD, Molecular Neurobiology, Box 5180, Baltimore, MD 21224, USA. E-mail: guhlȰintra.nida.nih. gov This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains. [56][57][58][59] These studies revealed an exquisite DAT-dependence of cocaine's locomotor stimulation. By contrast, they also produced surprising results that refuted the strong 'DAT-is-it' hypothesis of cocaine reward. Cocaine-induced locomotion: DAT is itDAT variation in humans a...

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“…[23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29, and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains.…”

mentioning

confidence: 99%

“…These authors also cited prior work from lesion studies 9-12 and electrical brain stimulation studies [13][14][15][16][17] This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains.…”

mentioning

confidence: 99%

Cocaine, reward, movement and monoamine transporters

Uhl¹,

Hall²,

Sora³

2002

Mol Psychiatry

View full text Add to dashboard Cite

Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities. Cocaine is a prototypical psychomotor stimulant that increases locomotor activity and elevates mood with rewarding euphoria.1 It also produces fearful and jittery aversive effects in many who take it.2,3 Cocaine blocks monoamine uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET), and can also block ligand-and voltage-gated channels with somewhat lower potencies. 4 Understanding the relationships between cocaine's molecular actions and its psychomotor stimulant and aversive properties has remained surprisingly incomplete. This review focuses on recent advances in our understanding of the complex relationships between cocaine's molecular actions and its locomotor stimulant, rewarding and aversive properties.The 'DAT-is-it' hypothesis drove thinking about cocaine reward for at least a decade, ideas widely linked to Kuhar, Spealman and their colleagues 4-8 who gathered evidence from structure-activity relationships of transporter-blocking compounds with differential potencies at DAT, SERT and NET. They examined relationships between potencies of these compounds in tests of reward and binding affinities at each of the monoamine transporters. They each identified the best correlations for the rewarding effects of cocaine with DAT blockade. These authors also cited prior work from lesion studies 9-12 and electrical brain stimulation studies [13][14][15][16][17] This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains. [56][57][58][59] These studies revealed an exquisite DAT-dependence of cocaine's locomotor stimulation. By contrast, they also produced surprising results that refuted the strong 'DAT-is-it' hypothesis of cocaine reward. Cocaine-induced locomotion: DAT is itDAT variation in humans and mice links robustly with variation in both baseline locomotion and/or psychostimulant-induced locomotor activities. Three strains of DAT knockout ...

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Human and mouse dopamine transporter genes: conservation of 5′-flanking sequence elements and gene structures

Cited by 68 publications

References 39 publications

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1)

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1)

Cocaine, reward, movement and monoamine transporters

Cocaine, reward, movement and monoamine transporters

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