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

Accili, Domenico; Fishburn, C. Simone; Drago, John; Steiner, Heinz; Lachowicz, Jean E.; Park, Bae-Hang; Gauda, Estelle B.; Lee, E. J.; Cool, Martha H.; Sibley, David R.; Gerfen, C. R.; Westphal, Heiner; Fuchs, Sara

doi:10.1073/pnas.93.5.1945

Cited by 425 publications

(274 citation statements)

References 29 publications

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“…At the behavioral level, the originally described increased spontaneous locomotor activity exhibited by D3R mutant mice (Accili et al, 1996;Xu et al, 1997) has been replicated by some studies (Betancur et al, 2001;Boulay et al, 1999;Vallone et al, 2002) but not others (Joseph et al, 2002;Jung et al, 1999;McNamara et al, 2002). A significant increase in novelty-induced stereotypy has also been observed in D3R mutant mice relative to wild-type controls (Joseph et al, 2002).…”

Section: Introductionmentioning

confidence: 82%

“…An alternative approach to understanding the behavioral function of the D3R has been the use of D3R knockout mice (reviewed in Holmes et al, 2004). Three lines of mutant mice lacking the D3R have been independently generated (Accili et al, 1996;Jung et al, 1999;Xu et al, 1997). D3R mutant mice exhibit normal D1R and D2R binding profiles and brain distributions (Accili et al, 1996;Xu et al, 1997;Wong et al, 2003), suggesting that effects on DA signaling in adult mice following selective mutation of the D3R are mediated primarily through loss of D3R expression.…”

Section: Introductionmentioning

confidence: 99%

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Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

McNamara

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Stanford

et al. 2006

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Accumulating evidence suggests that dopamine D3 receptor (D3R) stimulation is inhibitory to spontaneous and psychostimulant-induced locomotion through opposition of concurrent D1R and D2R-mediated signaling. To evaluate this model, we used homozygous D3R mutant mice and wildtype controls to investigate the role of the D3R in locomotor activity and stereotypy stimulated by acute amphetamine (AMPH) (0.2, 2.5, 5.0, 10.0 mg/kg). At the lowest dose tested (0.2 mg/kg), neither D3R mutant mice nor wild-type mice exhibited measurable change in locomotor activity or stereotypy relative to their respective saline-treated controls. D3R mutant mice exhibited a significantly greater increase in locomotor activity, but not stereotypy, relative to wild-type mice in response to treatment with AMPH 2.5 mg/kg. AMPH-induced locomotor activity and stereotypy were similar in both wild-type and D3R mutant mice at both the 5.0 and 10 mg/kg AMPH doses. These findings provide further support for an inhibitory role for the D3R in AMPH-induced locomotor activity, and demonstrate a more limited role for the D3R in modulating AMPH-induced stereotypy.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

McNamara

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Stanford

et al. 2006

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“…288 Additionally, antipsychotics with relatively low D3 affinity, such as clozapine, are reported to cause significantly lower movement disorders in contrast to first-generation antipsychotics, characterized by strong dopamine antagonism. 87,176,289 Polymorphisms in D3 receptors were first reported to contribute to drug-induced TD by Steen et al 230 and by Segman et al 231 In both studies, individuals with one or two copies of the Gly allele of a D 3 Ser9Gly polymorphism were more likely to develop TD with antipsychotic treatment.…”

Section: Prediction Of Side Effectsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…D2R mice were genotyped by PCR according to the protocol previously described (Díaz-Torga et al, 2002). D3R mutant mice (Accili et al, 1996), original strain B6.129S4-Drd3 tm1Dac , were also imported from The Jackson Laboratory. The mice were incipient congenic (N5 C57BL/6J D3R), having been backcrossed five times with the inbred strain C57BL/6J at the time of importation.…”

Section: Animalsmentioning

confidence: 99%

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

Doherty

Masten

Powell

et al. 2007

Neuropsychopharmacol

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Deficits in prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, are characteristics of schizophrenia and related neuropsychiatric disorders. Previous studies in mice demonstrate a contribution of dopamine (DA) D 1 -family receptors in modulating PPI and DA D 2 receptors (D2R) in mediating the PPI-disruptive effects of amphetamine. To examine further the contributions of DA receptor subtypes in PPI, we used a combined pharmacological and genetic approach. In congenic C57BL/6 J wildtype mice, we tested whether the D1R antagonist SCH23390 or the D2/3R antagonist raclopride would attenuate the effects of the indirect DA agonist cocaine (40 mg/kg). Both the D1R and D2/3R antagonists attenuated the cocaine-induced PPI deficit. We also tested the effect of cocaine on PPI in wild-type and DA D1R, D2R, or D3R knockout mice. The cocaine-induced PPI deficit was influenced differently by the three DA receptor subtypes, being absent in D1R knockout mice, partially attenuated in D2R knockout mice, and exaggerated in D3R knockout mice. Thus, the D1R is necessary for the PPI-disruptive effects of cocaine, while the D2R partially contributes to these effects. Conversely, the D3R appears to inhibit the PPI-disruptive effects of cocaine. Uncovering neural mechanisms involved in PPI will further our understanding of substrates of sensorimotor gating and could lead to better therapeutics to treat complex cognitive disorders such as schizophrenia.

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

Cited by 425 publications

References 29 publications

Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

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