The Influence of Genetic Variants on Striatal Dopamine Transporter and D2 Receptor Binding after TB

Wagner, Amy K.; Scanlon, Joelle M.; Becker, Carl; Ritter, Anne C.; Niyonkuru, Christian; Dixon, C. Edward; Conley, Yvette P.; Price, Julie C.

doi:10.1038/jcbfm.2014.87

Cited by 54 publications

(42 citation statements)

References 45 publications

(73 reference statements)

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“…In addition, a large proportion of the sample in Laruelle et al (1998) were patients with schizophrenia, some of whom may have been taking neuroleptics that increase D2/D3R availability in schizophrenia (Silvestri et al, 2000). Two other previous studies did not find differences in baseline D2/D3R availability between A1+ and A1− (Brody et al, 2006; Wagner et al, 2014) but these included diseased populations including smokers (Brody et al, 2006) and traumatic brain injured individuals (Wagner et al, 2014). Variability in D2/D3R availability measurement due to small sample sizes may have contributed to null findings in these studies.…”

Section: Discussionmentioning

confidence: 92%

“…Indeed, the A1 allele of the DRD2/ANKK1 TaqIA A1 variant has been associated with lower striatal D2/D3R availability relative to the A2 allele in several postmortem (Noble et al, 1991; Thompson et al, 1997; Ritchie and Noble, 2003; Gluskin and Mickey, 2016) and in vivo PET studies (Pohjalainen et al, 1998; Jonsson et al, 1999; Hirvonen et al, 2009a; Savitz et al, 2013; Gluskin and Mickey, 2016). However, a SPECT study (Laruelle et al, 1998) and two PET studies (Brody et al, 2006; Wagner et al, 2014) did not find this association, likely due to study of diseased populations (Gluskin and Mickey, 2016). To date, studies have used PET radioligands (e.g.…”

Section: Introductionmentioning

confidence: 94%

“…To date, studies have used PET radioligands (e.g. [ 11 C]raclopride (Thompson et al, 1997; Pohjalainen et al, 1998; Jonsson et al, 1999; Brody et al, 2006; Hirvonen et al, 2009a; Savitz et al, 2013; Wagner et al, 2014), [ 3 H]spiperone (Noble et al, 1991; Ritchie and Noble, 2003)) and the SPECT radioligand [ 123 I]IBZM (Laruelle et al, 1998), which do not discriminate between D2R and D3R and whose binding is affected by synaptic dopamine concentrations, leaving the link between DRD2/ANKK1 TaqIA genotype and D2R specific binding unclear. The novel PET radioligand ( N -[ 11 C]methyl)benperidol ([ 11 C]NMB) specifically binds to D2R in a reversible manner, does not undergo agonist-mediated internalization, is resistant to displacement by endogenous DA, and is selective for D2R over D3R by 200-fold (Moerlein et al, 1997; Karimi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

Eisenstein

Bogdan

Love‐Gregory

et al. 2016

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In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. GRAPHICAL ABSTRACT We investigated the difference in striatal dopamine D2 receptor binding, as measured by PET with (N-[11C]methyl)benperidol ([11C]NMB), between A1 allele carriers (A1+) and individuals homozygous for the A2 allele (A1−) of the DRD2/ANKK1 TaqIA single nucleotide polymorphism. In Study 1, A1+ had 5-12% less striatal [11C]NMB binding than A1−.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

Eisenstein

Bogdan

Love‐Gregory

et al. 2016

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“…This finding is not surprising since this SNP explains only a small percent of the variance in BMI of the population, making larger samples, and more accurate measures of adiposity necessary to observe reliable associations. In addition to obesity the A1 allele is associated with a number of disorders in which DA signaling is affected including attention deficit hyper activity disorder (ADHD) [65], addiction [66], alcoholism [67], poorer outcomes following traumatic brain injury [68, 69] and Parkinson’s disease [70]. …”

Section: Taqia Polymorphism (Rs1800497)mentioning

confidence: 99%

DRD2: Bridging the Genome and Ingestive Behavior

Sun

Luquet

2017

Trends in Cognitive Sciences

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Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) plays a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. We consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene * environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on dopamine receptor subtype 2 signaling.

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“…Multiple clinical studies show that striatal DA transporter binding is decreased among individuals up to one year after severe TBI, even in cases where no anatomical evidence of direct striatal injury exists [25, 26]. A transient decrease in striatal D1 receptors immediately after injury, followed by a subsequent return to pre-injury levels has also been reported in experimental TBI [27].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury

Markos

Failla

Ritter

et al. 2017

Journal of Head Trauma Rehabilitation

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Introduction Traumatic brain injury (TBI) frequently results in impaired cognition, a function that can be modulated by monoaminergic signaling. Genetic variation among monoaminergic genes may affect post-TBI cognitive performance. The vesicular monoamine transporter 2 (VMAT2) gene may be a novel source of genetic variation important for cognitive outcomes post-TBI given VMAT2’s role in monoaminergic neurotransmission. Objective Evaluate associations between VMAT2 variability and cognitive outcomes post-TBI. Methods We evaluated 136 white adults with severe TBI for variation in VMAT2 using a tagging single nucleotide polymorphism (tSNP) approach (rs363223, rs363226, rs363251, and rs363341). We show genetic variation interacts with assessed cognitive impairment [cognitive composite T-scores (Comp-Cog)] to influence functional cognition [Functional Independence Measure Cognitive subscale (FIM-Cog)] 6 and 12 months post-injury. Results Multivariate analyses at 6-months post-injury showed rs363226 genotype was associated with Comp-Cog (p=0.040) and interacted with Comp-Cog to influence functional cognition (p<0.001). G-homozygotes had the largest cognitive impairment, and their cognitive impairment had the greatest adverse effect on functional cognition. Discussion We provide the first evidence that genetic variation within VMAT2 is associated with cognitive outcomes following TBI. Further work is needed to validate this finding and elucidate mechanisms by which genetic variation affects monoaminergic signaling, mediating differences in cognitive outcomes.

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The Influence of Genetic Variants on Striatal Dopamine Transporter and D2 Receptor Binding after TB

Cited by 54 publications

References 45 publications

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

DRD2: Bridging the Genome and Ingestive Behavior

Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury

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