Overview

DAT-CI mice contain a triple mutation in the dopamine transporter gene rendering them insensitive to cocaine.

Donating Investigator

Howard Gu, Ohio State University

Genetic overview

Genetic Background	Generation

Slc6a3^tm1Hhg

Allele Type	Gene Symbol	Gene Name
Targeted (Hypomorph, Inserted expressed sequence)	Slc6a3	solute carrier family 6 (neurotransmitter transporter, dopamine), member 3

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Research Applications

Cell Biology Research
Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

DAT-CI mice contain the amino acid mutations L104V/F105C/A109V in exon 3 of the solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (Slc6a3) gene. Slc6a3 encodes the dopamine transporter (DAT) which pumps the neurotransmitter dopamine out of the synapse back into cytosol. Dopamine release in the ventral tegmental area (VTA) plays a major role in reward-motivated behavior. Defects in dopamine transport reduces the rate of transport from the synapse, thus increasing the levels of dopamine in the brain. DAT has been implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, and alcoholism. Cocaine is able to block this transport, by binding directly to the DAT, increasing reward-related dopamine activity. DAT-CI mice contain a triple mutation in the transmembrane domain 2 (TM2) of the dopamine transporter introducing a conformational change on the protein structure. These mice retain a functional DAT that is rendered insensitive to cocaine. DAT-CI DAT is 70-fold more insensitive to cocaine inhibition than WT mice.

Development

A targeting construct was designed to insert a loxP-flanked neomycin (neo) resistance cassette downstream of exon 3 of the solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (Slc6a3) gene. The triple mutation L104V/F105C/A109V was introduced in exon 3. This targeting construct was electroporated into 129X1/SvJ-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric males were bred to C57BL/6J females and offspring were subsequently bred to FVB/N-Tg(EIIa-cre)C5379Lmgd/J mice (Stock No. 003314) to remove the floxed neo cassette. These DAT-CI mice were bred to C57BL/6J mice for at least 20 generations. Upon arrival at The Jackson Laboratory, mutant mice were bred to C57BL/6J mice (Stock No. 000664) for at least one generation to establish the colony.

Control Suggestions

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Chen R; Tilley MR; Wei H; Zhou F; Zhou FM; Ching S; Quan N; Stephens RL; Hill ER; Nottoli T; Han DD; Gu HH. 2006. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc Natl Acad Sci U S A 103(24):9333-8PubMed: 16754872 MGI: J:111041

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Genetics

Slc6a3^tm1Hhg

Allele Symbol: Slc6a3^tm1Hhg

Allele Name	targeted mutation 1, Howard H Gu
Allele Type	Targeted (Hypomorph, Inserted expressed sequence)
Allele Synonym(s)	Slc6a3^tm1Hhg; targeted mutation 1, Howard H Gu
Gene Symbol and Name	Slc6a3, solute carrier family 6 (neurotransmitter transporter, dopamine), member 3
Gene Synonym(s)	DAT; dopamine transporter 1; DAT1; PKDYS; Dat1; Dat1; PKDYS1
Strain of Origin	129X1/SvJ
Chromosome	13
Molecular Note	A loxP-flanked neo was inserted into intron 3 with the L104V, F105C, and A109V mutations. The neo was subsequently removed from the locus.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

attention deficit hyperactivity disorder

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Cell Biology Research
- Channel and Transporter Defects
Neurobiology Research
- Channel and Transporter Defects
- Behavioral and Learning Defects
- Receptor Defects
  - dopamine receptor

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Slc6a3^tm1Hhg/Slc6a3^tm1Hhg
involves: 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

abnormal locomotor activation
- 10 mg/kg morphine or amphetamine stimulated locomotor activity in mutants but not in wild-type
- doses of cocaine from 10-40 mg/kg had no effect on mutants but increased activity significantly in wild-type mice; cocaine induced locomotor suppression in a dose-dependent fashion in mutants

hyperactivity
- mutants display higher baseline motor activity than wild-type

impaired conditioned place preference behavior
- 2.5 mg/kg of amphetamine induces similar levels of CPP in mutants and wild-type
- mutants given four injections of 5 and 20 mg/kg cocaine fail to develop a conditioned placement preference compared to robust CPP in wild-type at these doses

homeostasis/metabolism phenotype

increased dopamine level
- extracellular dopamine concentrations in freely-moving mice measured by microdialysis are 64% higher than in wild-type mice

nervous system phenotype

abnormal dopaminergic neuron morphology
- spontaneous firing by wild-type dopaminergic neurons in brain slices is inhibited by 53.2% by a dose of 5 um cocaine but there is no significant effect on mutant neurons

abnormal neurotransmitter uptake
- in synaptosomal uptake assays, the mutant dopamine transporters are 89-fold more sensitive to cocaine inhibition than those from wild-type mice

abnormal synaptic dopamine release
- amplitude of dopamine release is 25% lower and decay is 3-fold slower in mutants compared to wild-type as assessed by fast cyclic voltammetry
- release of dopamine in response to amphetamine is lower than in wild-type

The following phenotype relates to a compound genotype created using this strain

Genotype: Slc6a3^tm1Hhg/Slc6a3^tm1Hhg
B6.129X1-Slc6a3

behavior/neurological phenotype

hyperactivity
- in an open-field test, mutants display higher horizontal activity than controls

nervous system phenotype

abnormal CNS synaptic transmission
- sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA-mediated synaptic currents in the striatum is lost, however CB1Rs modulating glutamate transmission and GABAB receptors are not affected

abnormal inhibitory postsynaptic currents
- cocaine or sucrose are unable to alter the HU210 effects on sIPSCs as they do in control mice
- Normal - however, the GABAB receptor agonist baclofen has the same effect as in controls
- the effects of CB1R agonist HU210 on striatal neuron spontaneous inhibitory postsynaptic currents (sIPSCs) and evoked inhibitory postsynaptic currents (eIPSCs) are abolished, indicating loss of sensitivity of CB1Rs(GABA)

abnormal miniature inhibitory postsynaptic currents
- dihydroxyphenylglycine treatment does not inhibit striatal miniature inhibitory postsynaptic current (mIPSC) frequency as in wild-type mice

References

Chen R; Tilley MR; Wei H; Zhou F; Zhou FM; Ching S; Quan N; Stephens RL; Hill ER; Nottoli T; Han DD; Gu HH. 2006. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc Natl Acad Sci U S A 103(24):9333-8PubMed: 16754872 MGI: J:111041

Additional - Slc6a3^tm1Hhg related

Technical Support

Contact Technical Support

Genotyping Protocols
- Standard PCR:Slc6a3^tm1Hhg
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, homozygous mice may be bred together.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129X1(FVB)-Slc6a3^tm1Hhg/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #024165 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or wildtype for Slc6a3<tm1Hhg>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

Related Products and Services

Frozen Mouse Embryo	B6.129X1(FVB)-Slc6a3<tm1Hhg>/J	$2595.00
Frozen Mouse Embryo	B6.129X1(FVB)-Slc6a3<tm1Hhg>/J	$2595.00
Frozen Mouse Embryo	B6.129X1(FVB)-Slc6a3<tm1Hhg>/J	$3373.50
Frozen Mouse Embryo	B6.129X1(FVB)-Slc6a3<tm1Hhg>/J	$3373.50

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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General Terms and Conditions

Questions about Terms of Use

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Licensing Information

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Slc6a3tm1Hhg

Allele Symbol: Slc6a3tm1Hhg

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Slc6a3tm1Hhg/Slc6a3tm1Hhginvolves: 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

homeostasis/metabolism phenotype

nervous system phenotype

Genotype: Slc6a3tm1Hhg/Slc6a3tm1HhgB6.129X1-Slc6a3

behavior/neurological phenotype

nervous system phenotype

References

Additional - Slc6a3tm1Hhg related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Slc6a3^tm1Hhg

Allele Symbol: Slc6a3^tm1Hhg

Genotype: Slc6a3^tm1Hhg/Slc6a3^tm1Hhg
involves: 129X1/SvJ * C57BL/6J

Genotype: Slc6a3^tm1Hhg/Slc6a3^tm1Hhg
B6.129X1-Slc6a3

Additional - Slc6a3^tm1Hhg related