Description

Strain Information

Type Congenic; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Malcolm Low,   Oregon Health Sciences University

Description
Mice homozygous for this targeted mutation (D4R-/-) are viable and fertile. With exon 2 of the mutant locus deleted, the truncated transcript is predicted to produce a 131 amino acid mutant polypeptide. Homozygous mice may exhibit locomotor supersensitivity to ethanol, cocaine, and methamphetamine, as well as alterations in dopamine synthesis and function, glutamate levels and metabolism, behavioral responses to novelty, and spontaneous locomotor activity in both novel and familiar environments. These D4R-mutant mice may be useful in studying dopamine/neurotransmitter function, drug addiction, Parkinson's disease, and schizophrenia or other psychoses.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
A targeting vector was designed to replace exon 2 of the targeted gene with a neomycin resistance cassette. The construct was electroporated into 129P2/OlaHsd-derived E14TG2A embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and chimeric males were bred to C57BL/6J females. Heterozygous D4R-mutant mice were bred to wildtype siblings or C57BL/6J mice for approximately 30 generations (including to C57BL/6J for 5 most recent generations) prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred to C57BL/6J for at least one generation to establish the colony.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Drd4^tm1Dkg/Drd4^tm1Dkg

        involves: 129P2/OlaHsd * C57BL/6J

• behavior/neurological phenotype
• decreased exploration in new environment (MGI Ref ID J:76023)
  • in the open field test, homozygotes make fewer entries into the center, but do not differ in overall levels of activity relative to wild-type mice
  • in the emergence test, homozygotes spend more time in the cylinder and make fewer entries into the cylinder relative to wild-type mice
  • in the novel object test, homozygotes exhibit a smaller increase in % of time spent in the center after introduction of the cup relative to wild-type mice
  • overall, homozygotes display the largest reductions in behavioral responses to novelty in the test that maximizes approach behaviors (novel object test), and the smallest reductions in the test that maximizes avoidance behavior (open field test)
• decreased vertical activity (MGI Ref ID J:43061)
  • homozygotes exhibit fewer rearing episodes in an open field environment relative to wild-type mice
• enhanced coordination (MGI Ref ID J:43061)
  • homozygotes outperform their wild-type littermates on the rotarod, with 50% fewer falls and a 2.5-fold increase in the length of time remaining on the rotarod
• hyperactivity elicited by ethanol administration (MGI Ref ID J:43061)
  • homozygotes are supersensitive to the locomotor-stimulating effects of ethanol (20% v/v) relative wild-type mice
• hypoactivity (MGI Ref ID J:43061)
  • homozygotes cover less horizontal distance, initiate fewer movements and spend less time in motion in an open field environment relative to wild-type mice
  • female homozygotes appear to be slightly more active than males
• increased sensitivity to addictive substance (MGI Ref ID J:43061)
  • homozygotes display a dose-dependent hypersensitivity to the locomotor-stimulating effects of cocaine and methamphetamine
• homeostasis/metabolism phenotype
• decreased sensitivity to xenobiotics (MGI Ref ID J:43061)
  • unlike wild-type, catecholamine-depleted, akinetic-rendered homozygotes fail to exhibit a 40% suppression of apomorphine-induced locomotor activity in response to 0.6 mg/kg clozapine
  • however, both genotypes of mice exhibit completely loss of apomorphine-induced locomotion in response to 6 mg/kg clozapine
• nervous system phenotype
• increased dopamine level (MGI Ref ID J:43061)
  • following DOPA decarboxylase inhibition, homozygotes accumulate more L-DOPA in the dorsal striatum-caudate putamen (CPU) relative to wild-type mice
  • homozygotes exhibit elevated dopamine synthesis and its conversion to DOPAC in the dorsal striatum, as shown by a 93% increase of DOPAC content in CPU and a 1.9-fold increase in DOPAC/DA ratio relative to wild-type mice

View Research Applications

Research Applications

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

Neurobiology Research
Behavioral and Learning Defects (genes regulating preferences to alcohol)
Parkinson's Disease
Receptor Defects (dopamine receptor)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Drd4tm1Dkg
Allele Name		targeted mutation 1, David K Grandy
Allele Type		Targeted (knock-out)
Common Name(s)		D4KO; D4R -; Drd4-;
Mutation Made By		David Grandy,   Oregon Heath Sciences University
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14TG2a
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Drd4, dopamine receptor 4
Chromosome		7
Gene Common Name(s)		AW125663; D4DR; D4R; D4RA; Drd-4; expressed sequence AW125663;
Molecular Note		A neomycin resistance cassette replaced exon 2. RT-PCR analysis demonstrated that a mutated transcript was produced from this allele that spliced exon 1 to exon 3. This mutation causes a shift in the reading frame that is predicted to result in the production of a truncated protein. [MGI Ref ID J:43061]

Genotyping

Genotyping Information

Genotyping Protocols

Drd4^tm1Dkg, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Helms CM; Gubner NR; Wilhelm CJ; Mitchell SH; Grandy DK. 2008. D(4) receptor deficiency in mice has limited effects on impulsivity and novelty seeking. Pharmacol Biochem Behav 90(3):387-93. [PubMed: 18456309]  [MGI Ref ID J:136871]

Kruzich PJ; Suchland KL; Grandy DK. 2004. Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine. Synapse 53(2):131-9. [PubMed: 15170825]  [MGI Ref ID J:136873]

Rubinstein M; Phillips TJ; Bunzow JR; Falzone TL; Dziewczapolski G ; Zhang G ; Fang Y ; Larson JL ; McDougall JA ; Chester JA ; Saez C ; Pugsley TA ; Gershanik O ; Low MJ ; Grandy DK. 1997. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90(6):991-1001. [PubMed: 9323127]  [MGI Ref ID J:43061]

Thomas TC; Grandy DK; Gerhardt GA; Glaser PE. 2008. Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum. Neuropsychopharmacology :. [PubMed: 18536704]  [MGI Ref ID J:136870]

Thomas TC; Kruzich PJ; Joyce BM; Gash CR; Suchland K; Surgener SP; Rutherford EC; Grandy DK; Gerhardt GA; Glaser PE. 2007. Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release. J Neurosci Methods 166(2):306-14. [PubMed: 17449106]  [MGI Ref ID J:136872]

Additional References

Drd4^tm1Dkg related

Bek MJ; Wang X; Asico LD; Jones JE; Zheng S; Li X; Eisner GM; Grandy DK; Carey RM; Soares-da-Silva P; Jose PA. 2006. Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice. Hypertension 47(2):288-95. [PubMed: 16380537]  [MGI Ref ID J:135774]

Cepeda C; Hurst RS; Altemus KL; Flores-Hernandez J; Calvert CR; Jokel ES; Grandy DK; Low MJ; Rubinstein M; Ariano MA; Levine MS. 2001. Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice. J Neurophysiol 85(2):659-70. [PubMed: 11160501]  [MGI Ref ID J:103965]

Dulawa SC; Grandy DK; Low MJ; Paulus MP; Geyer MA. 1999. Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 19(21):9550-6. [PubMed: 10531457]  [MGI Ref ID J:76023]

Falzone TL; Gelman DM; Young JI; Grandy DK; Low MJ; Rubinstein M. 2002. Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci 15(1):158-64. [PubMed: 11860516]  [MGI Ref ID J:89406]

Gan L; Falzone TL; Zhang K; Rubinstein M; Baldessarini RJ; Tarazi FI. 2004. Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice. J Mol Neurosci 22(3):167-78. [PubMed: 14997010]  [MGI Ref ID J:121245]

Katz JL; Chausmer AL; Elmer GI; Rubinstein M; Low MJ; Grandy DK. 2003. Cocaine-induced locomotor activity and cocaine discrimination in dopamine D4 receptor mutant mice. Psychopharmacology (Berl) 170(1):108-14. [PubMed: 12783155]  [MGI Ref ID J:103880]

Nir I; Harrison JM; Haque R; Low MJ; Grandy DK; Rubinstein M; Iuvone PM. 2002. Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci 22(6):2063-73. [PubMed: 11896146]  [MGI Ref ID J:75589]

Pozdeyev N; Tosini G; Li L; Ali F; Rozov S; Lee RH; Iuvone PM. 2008. Dopamine modulates diurnal and circadian rhythms of protein phosphorylation in photoreceptor cells of mouse retina. Eur J Neurosci 27(10):2691-700. [PubMed: 18547251]  [MGI Ref ID J:137182]

Ralph RJ; Varty GB; Kelly MA; Wang YM; Caron MG; Rubinstein M ; Grandy DK ; Low MJ ; Geyer MA. 1999. The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci 19(11):4627-33. [PubMed: 10341260]  [MGI Ref ID J:55027]

Rubinstein M; Cepeda C; Hurst RS; Flores-Hernandez J; Ariano MA; Falzone TL; Kozell LB; Meshul CK; Bunzow JR; Low MJ; Levine MS; Grandy DK. 2001. Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J Neurosci 21(11):3756-63. [PubMed: 11356863]  [MGI Ref ID J:69457]

Seeman P; Weinshenker D; Quirion R; Srivastava LK; Bhardwaj SK; Grandy DK; Premont RT; Sotnikova TD; Boksa P; El-Ghundi M; O'dowd BF; George SR; Perreault ML; Mannisto PT; Robinson S; Palmiter RD; Tallerico T. 2005. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A 102(9):3513-8. [PubMed: 15716360]  [MGI Ref ID J:96985]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

 

This strain is currently Under Development for Distribution Colony.
To register your interest in this strain go to the Strain Interest Form.

Estimated Available for Sale Date:

Please note: Estimated available for sale dates are provided to keep customers better informed on strains under development. Please note that our Colony Managers routinely monitor the target date and edit it based on breeding performance and other factors. The length of time it takes to make a new strain available for sale depends on genotype, age, number of animals sent by the Donating Investigator, breeding performance, additional strain development (backcrossing, making homozygous), and anticipated demand for the strain/interest registered.

View All Strains Under Development and On Hold

Supply Details

Standard Supply	Under Development for Distribution Colony
Supply Notes	This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

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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Terms of Use

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For Licensing and Use Restrictions view the link(s) below:
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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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