Possible involvement of alpha‐2A adrenergic receptors in attention deficit hyperactivity disorder: Radioligand binding and polymorphism studies

Deupree, Jean D.; Smith, Shelley D.; Kratochvil, Christopher J.; Bohac, Daryl L.; Ellis, Christopher R.; Polaha, Jodi; Bylund, David B.

doi:10.1002/ajmg.b.30371

Cited by 38 publications

(27 citation statements)

References 57 publications

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“…In fact, clonidine, which decreases NE activity, has been reported to be of benefit in ADHD and is now in a Phase III clinical trial for treatment of ADHD (http://clinicaltrials.gov/show/NCT00031395). Our evidence suggests that a decrease in α2-adrenergic autoreceptor control of NE activity underlies noradrenergic hyperfunction in our rat model of prenatal cocaine, so it is interesting that a similar deficit appears to occur in the spontaneously hypertensive rat model of ADHD (Russell, 2002) and that a decreased density and decreased affinity of binding to α2-adrenergic sites have been reported in ADHD (Shekim et al, 1994;Deupree et al, 2006). Moreover, there is evidence supporting association and linkage of α2A-adrenergic receptor gene polymorphisms with ADHD (Park et al, 2005).…”

Section: Discussionsupporting

confidence: 61%

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

et al. 2007

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Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily intravenous injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [ 125 I]-para-iodoclonidine, a radioligand with specificity for high affinity α2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared to prenatal saline controls. As α 2 -adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.

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Section: Discussionsupporting

confidence: 61%

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

et al. 2007

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“…Since this initial study, nine independent studies have been published examining the association of ADHD with this SNP and additional polymorphisms within ADRA2A (Bobb et al 2005;Brookes et al 2006a;Cho et al 2008b;Deupree et al 2006;Guan et al 2008;Park et al 2005;Roman et al 2003;Schmitz et al 2006;Stevenson et al 2005). In the present review, we conducted a meta-analysis of studies testing for association between ADHD and 3 ADRA2A polymorphisms (rs1800544, rs1800545, and rs553668).…”

Section: Alpha 2a Adrenergic Receptor (Adra2a)mentioning

confidence: 99%

“…For the meta-analysis of association between childhood ADHD and the ADRA2A MspI restriction polymorphism (rs1800544), data from Wve TDT (Brookes et al 2006a;Deupree et al 2006;Park et al 2005;Wang et al 2006;Xu et al 2001) and six Case-Control/HHRR (Bobb et al 2005;Cho et al 2008b;Guan et al 2008;Roman et al 2003;Schmitz et al 2006;Stevenson et al 2005) studies were included, with the G allele considered the "high-risk" allele based on previous research (Park et al 2005). Results of this meta-analysis, shown in Fig.…”

Section: Alpha 2a Adrenergic Receptor (Adra2a)mentioning

confidence: 99%

Candidate gene studies of ADHD: a meta-analytic review

2009

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Quantitative genetic studies (i.e., twin and adoption studies) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder (ADHD). Over the past 15 years, considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD. The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies. The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results. Significant associations were identified for several candidate genes including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25. Further, significant heterogeneity was observed for the associations between ADHD and DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA, and SNAP25, suggesting that future studies should explore potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors). We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD.

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“…According to a recent study by Schmitz et al [2006], those subjects who were homozygous for the G allele had significantly higher odds ratios for the inattentive subtype of ADHD than did those with other genotypes (C/C þ C/G genotypes). With respect to the DraI polymorphism, Park et al [2005] reported the preferential transmission of the T allele of this polymorphism in children with ADHD combined subtype, and Deupree et al [2006] observed significant linkage disequilibrium with this polymorphism and the inattentive or hyperactive phenotypes of ADHD.…”

Section: Introductionmentioning

confidence: 99%

Possible association of the alpha‐2A‐adrenergic receptor gene with response time variability in attention deficit hyperactivity disorder

Cho

Kim

et al. 2008

American J of Med Genetics Pt B

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Previous studies have demonstrated that the MspI and DraI polymorphisms at the alpha-2A-adrenergic receptor gene (ADRA2A) are associated with ADHD. However, few studies have been designed to ascertain the association between the ADRA2A genotypes and the performance on neurocognitive measures in ADHD. The aims of this study were to examine the association of the ADRA2A MspI and DraI polymorphisms with ADHD in Korean subjects, and to determine the relationship between the genotypes of these two polymorphisms and the candidate endophenotypes, as measured by the continuous performance test (CPT). In a case-control study, we assessed 186 ADHD probands and 150 normal controls. One hundred eight trios were studied in a family based association analysis. The transmission disequilibrium test (TDT) analysis showed preferential transmission of the C allele of the DraI polymorphism (chi(2) = 5.88, P = 0.015). In the haplotype analyses, a trend of over-transmission of haplotype C/C was observed (chi(2) = 3.80, P = 0.051). The homozygous subjects for the C allele (C/C genotype) at the DraI polymorphism showed a trend toward a higher mean T-score with respect to the response time variability profiles of the CPT than did those with the other genotypes (C/T + T/T genotypes; P = 0.042). The homozygous subjects for the G allele (G/G genotype) at the MspI polymorphism showed a tendency to have a lower mean T-score with respect to the response time variability profiles of the CPT (P = 0.068). The results of this study provide important evidence for the involvement of the ADRA2A MspI and DraI polymorphisms in the etiology of ADHD in Korean subjects. In addition, our results provide evidence for the possible role of these two polymorphisms in ADHD symptom expression, such as increased response time variability.

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Possible involvement of alpha‐2A adrenergic receptors in attention deficit hyperactivity disorder: Radioligand binding and polymorphism studies

Cited by 38 publications

References 57 publications

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Candidate gene studies of ADHD: a meta-analytic review

Possible association of the alpha‐2A‐adrenergic receptor gene with response time variability in attention deficit hyperactivity disorder

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