• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Mar 5, 1996; 93(5): 1945–1949.
PMCID: PMC39888

A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice.

Abstract

While most effects of dopamine in the brain are mediated by the D1 and D2 receptor subtypes, other members of this G protein-coupled receptor family have potentially important functions. D3 receptors belong to the D2-like subclass of dopamine receptors, activation of which inhibits adenylyl cyclase. Using targeted mutagenesis in mouse embryonic stem cells, we have generated mice lacking functional D3 receptors. A premature chain-termination mutation was introduced in the D3 receptor gene after residue Arg-148 in the second intracellular loop of the predicted protein sequence. Binding of the dopamine antagonist [125I]iodosulpride to D3 receptors was absent in mice homozygous for the mutation and greatly reduced in heterozygous mice. Behavioral analysis of mutant mice showed that this mutation is associated with hyperactivity in an exploratory test. Homozygous mice lacking D3 receptors display increased locomotor activity and rearing behavior. Mice heterozygous for the D3 receptor mutation show similar, albeit less pronounced, behavioral alterations. Our findings indicate that D3 receptors play an inhibitory role in the control of certain behaviors.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Sibley DR, Monsma FJ., Jr Molecular biology of dopamine receptors. Trends Pharmacol Sci. 1992 Feb;13(2):61–69. [PubMed]
  • Sunahara RK, Seeman P, Van Tol HH, Niznik HB. Dopamine receptors and antipsychotic drug response. Br J Psychiatry Suppl. 1993 Dec;(22):31–38. [PubMed]
  • Sokoloff P, Schwartz JC. Novel dopamine receptors half a decade later. Trends Pharmacol Sci. 1995 Aug;16(8):270–275. [PubMed]
  • Gingrich JA, Caron MG. Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci. 1993;16:299–321. [PubMed]
  • Pilon C, Lévesque D, Dimitriadou V, Griffon N, Martres MP, Schwartz JC, Sokoloff P. Functional coupling of the human dopamine D3 receptor in a transfected NG 108-15 neuroblastoma-glioma hybrid cell line. Eur J Pharmacol. 1994 Jul 15;268(2):129–139. [PubMed]
  • Sokoloff P, Andrieux M, Besançon R, Pilon C, Martres MP, Giros B, Schwartz JC. Pharmacology of human dopamine D3 receptor expressed in a mammalian cell line: comparison with D2 receptor. Eur J Pharmacol. 1992 Apr 10;225(4):331–337. [PubMed]
  • Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990 Sep 13;347(6289):146–151. [PubMed]
  • Landwehrmeyer B, Mengod G, Palacios JM. Differential visualization of dopamine D2 and D3 receptor sites in rat brain. A comparative study using in situ hybridization histochemistry and ligand binding autoradiography. Eur J Neurosci. 1993 Feb 1;5(2):145–153. [PubMed]
  • Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC. Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res. 1991 Nov 15;564(2):203–219. [PubMed]
  • Landwehrmeyer B, Mengod G, Palacios JM. Dopamine D3 receptor mRNA and binding sites in human brain. Brain Res Mol Brain Res. 1993 Apr;18(1-2):187–192. [PubMed]
  • Diaz J, Lévesque D, Lammers CH, Griffon N, Martres MP, Schwartz JC, Sokoloff P. Phenotypical characterization of neurons expressing the dopamine D3 receptor in the rat brain. Neuroscience. 1995 Apr;65(3):731–745. [PubMed]
  • Sokoloff P, Martres MP, Giros B, Bouthenet ML, Schwartz JC. The third dopamine receptor (D3) as a novel target for antipsychotics. Biochem Pharmacol. 1992 Feb 18;43(4):659–666. [PubMed]
  • Caine SB, Koob GF. Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science. 1993 Jun 18;260(5115):1814–1816. [PubMed]
  • Guo N, Klitenick MA, Tham CS, Fibiger HC. Receptor mechanisms mediating clozapine-induced c-fos expression in the forebrain. Neuroscience. 1995 Apr;65(3):747–756. [PubMed]
  • Schmauss C, Haroutunian V, Davis KL, Davidson M. Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8942–8946. [PMC free article] [PubMed]
  • Drago J, Gerfen CR, Lachowicz JE, Steiner H, Hollon TR, Love PE, Ooi GT, Grinberg A, Lee EJ, Huang SP, et al. Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12564–12568. [PMC free article] [PubMed]
  • Park BH, Fishburn CS, Carmon S, Accili D, Fuchs S. Structural organization of the murine D3 dopamine receptor gene. J Neurochem. 1995 Feb;64(2):482–486. [PubMed]
  • Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, José PA, Taylor SI, Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet. 1996 Jan;12(1):106–109. [PubMed]
  • Fishburn CS, Belleli D, David C, Carmon S, Fuchs S. A novel short isoform of the D3 dopamine receptor generated by alternative splicing in the third cytoplasmic loop. J Biol Chem. 1993 Mar 15;268(8):5872–5878. [PubMed]
  • Scibilia RJ, Lachowicz JE, Kilts CD. Topographic nonoverlapping distribution of D1 and D2 dopamine receptors in the amygdaloid nuclear complex of the rat brain. Synapse. 1992 Jun;11(2):146–154. [PubMed]
  • Dryja TP. Doyne Lecture. Rhodopsin and autosomal dominant retinitis pigmentosa. Eye (Lond) 1992;6(Pt 1):1–10. [PubMed]
  • Daly SA, Waddington JL. Behavioural effects of the putative D-3 dopamine receptor agonist 7-OH-DPAT in relation to other "D-2-like" agonists. Neuropharmacology. 1993 May;32(5):509–510. [PubMed]
  • Svensson K, Carlsson A, Huff RM, Kling-Petersen T, Waters N. Behavioral and neurochemical data suggest functional differences between dopamine D2 and D3 receptors. Eur J Pharmacol. 1994 Oct 3;263(3):235–243. [PubMed]
  • Svensson K, Carlsson A, Waters N. Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release. J Neural Transm Gen Sect. 1994;95(1):71–74. [PubMed]
  • Waters N, Svensson K, Haadsma-Svensson SR, Smith MW, Carlsson A. The dopamine D3-receptor: a postsynaptic receptor inhibitory on rat locomotor activity. J Neural Transm Gen Sect. 1993;94(1):11–19. [PubMed]
  • Large CH, Stubbs CM. The dopamine D3 receptor: Chinese hamsters or Chinese whispers? Trends Pharmacol Sci. 1994 Feb;15(2):46–47. [PubMed]
  • Freedman JE, Waszczak BL, Cox RF, Liu JC, Greif GJ. The dopamine D3 receptor and 7-OH-DPAT. Trends Pharmacol Sci. 1994 Jun;15(6):173–174. [PubMed]
  • Xu M, Moratalla R, Gold LH, Hiroi N, Koob GF, Graybiel AM, Tonegawa S. Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell. 1994 Nov 18;79(4):729–742. [PubMed]
  • Baik JH, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis A, Le Meur M, Borrelli E. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature. 1995 Oct 5;377(6548):424–428. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Gene
    Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • OMIM
    OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...