Dopamine D4 Receptor Gene Novelty or Nonsense?

Paterson, Andrew D.; Sunohara, Glen; Kennedy, James L.

doi:10.1016/s0893-133x(98)00115-8

Cited by 153 publications

(86 citation statements)

References 78 publications

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“…For example, blood levels of lead positively correlated with the ADHD symptoms hyperactivity-impulsivity (Nigg et al, 2008). The functional consequences of DRD4 polymorphisms, and therefore possible mechanisms for interaction with environmental insults, are unclear (Paterson, 1999). In vitro, the receptor coded by DRD4.7 is slightly less sensitive to dopamine as indicated by reduced inhibition of cAMP relative to DRD4.2 or DRD4.4 (Asghari et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Domain III is affected by polymorphisms in human DRD4 and participates in coupling the receptor to G proteins and in receptor trafficking (Oldenhof et al, 1998). How polymorphisms affect receptor function in humans is unclear (Paterson, 1999). The absence of functional D 4 Rs in D 4 KO mice models is one possible functional consequence of the DRD4.7 polymorphism in humans.…”

Section: Nih Public Accessmentioning

confidence: 99%

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D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking

Helms

Gubner

Wilhelm

et al. 2008

Pharmacology Biochemistry and Behavior

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Alleles of the human dopamine D 4 receptor (D 4 R) gene (DRD4.7) have repeatedly been found to correlate with novelty seeking, substance abuse, pathological gambling, and attention deficit hyperactivity disorder (ADHD). If these various psychopathologies are a result of attenuated D 4 Rmediated signaling, mice lacking D 4 Rs (D 4 KO) should be more impulsive than wild-type (WT) mice and exhibit more novelty seeking. However, in our study, D 4 KO and WT mice showed similar levels of impulsivity as measured by delay discounting performance and response inhibition on a Go/Nogo test, suggesting that D 4 R-mediated signaling may not affect impulsivity. D 4 KO mice were more active than WT mice in the first 5 min of a novel open field test, suggesting greater novelty seeking but for both genotypes, with the more impulsive D 4 KO mice habituated less readily in the novel open field. These data suggest that the absence of D 4 Rs is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking. Keywords impulsivity; D 4 receptors; mice; delay discounting; Go/No-go; inhibition; novelty seeking; locomotion Psychopathologies including pathological gambling (Comings et al., 2001), substance abuse (Vandenbergh et al., 2000), opiate dependence (Kotler et al., 1997), and attention-deficit hyperactivity disorder (ADHD; Faraone et al., 2001;Grady et al., 2003) are associated with the presence of dopamine D 4 receptor (D 4 R) gene (DRD4) polymorphisms. Novelty-seeking is often associated with these psychopathologies and is also observed in individuals possessing DRD4 alleles containing 7 repeats of a 48-nucleotide sequence (DRD4.7) (Benjamin et al., 1996;Ebstein et al., 1996Ebstein et al., , 1997. Heightened levels of impulsivity is another common trait Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Evenden, 1999), but its association with the DRD4 gene is unknown. NIH Public AccessImpulsivity is thought to encompass multiple subcomponents functioning through distinct neural pathways. "Choice" impulsivity and "motor" impulsivity are two such subcomponents (Winstanley et al., 2004). "Choice" impulsivity refers to an intolerance for reward delays and is assessed by measuring relative preference for small, immediate over large, delayed rewards (Rachlin & Green, 1972;Ainslie, 1975;Logue, 1988) in rats (Bradshaw & Szabadi, 1992), mice (Isles et al., 2004;Helms et al., 2006), pigeons (Mazur, 1987, and humans (Rachlin et al., 1991;Green et al., 1994). Exaggerated preference for immediate rewards (heightened "delay discounting") is found in many of ...

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Section: Discussionmentioning

confidence: 99%

Section: Nih Public Accessmentioning

confidence: 99%

D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking

Helms

Gubner

Wilhelm

et al. 2008

Pharmacology Biochemistry and Behavior

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“…As an example, it has been suggested that the allelic variants of the dopamine D(4) receptor (DRD4) gene may be associated with novelty seeking, with longer variants being associated with the behavior. However, investigators are now suggesting that it may not be DRD4 genotype per se, but rather an interaction with substance use or abuse that is associated (for reviews, see Paterson et al, 2 Lusher et al, 3 and Kluger et al 4 ).…”

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Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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“…3 Nevertheless, there is still conflicting evidence whether the presence of the DRD4 exon III 7-repeat allele is associated with higher scores in Novelty Seeking. For example, our group confirmed this association in an earlier work, 4 but we did not observe an association between DRD4 exon III and Novelty Seeking in a recent study, 5 although both samples were drawn from the same population.…”

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confidence: 99%

Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants

et al. 2003

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Dopamine D4 Receptor Gene Novelty or Nonsense?

Abstract: Although the role of genetics in personality has

Cited by 153 publications

References 78 publications

D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking

D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants

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