Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD

Park, L; Nigg, Joel T.; Waldman, Irwin D.; Nummy, Katherine A.; Huang-Pollock, Cynthia L.; Rappley, Marsha D.; Friderici, Karen H.

doi:10.1038/sj.mp.4001605

Cited by 82 publications

(79 citation statements)

References 41 publications

(38 reference statements)

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“…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: Discussionmentioning

confidence: 91%

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: Discussionmentioning

confidence: 91%

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

et al. 2007

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“…However, studies involving Western populations have reported that the G allele of the MspI polymorphism and the T allele of the DraI polymorphism in ADRA2A are putative risk alleles in ADHD. 30,31 Ethnic differences in allele frequencies may be responsible for the discrepancies between populations, 29 and there is also a possibility that the pattern of linkage disequilibrium might differ among populations. 32 Divergent results among studies might also reflect methodologic issues, such as sample size, inclusion or exclusion criteria, or instruments used to assess symptom characteristics.…”

Section: Discussionmentioning

confidence: 99%

Regional differences in cerebral perfusion associated with the α-2A-adrenergic receptor genotypes in attention deficit hyperactivity disorder

Kim¹,

Kim²,

Kang

et al. 2010

jpn

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Background: Neurobiologic studies have suggested that dysregulation of central noradrenergic systems may be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD), and it has been hypothesized that genetic changes in the norepinephrine pathways might contribute to dysfunction of the prefrontal cortex circuits in ADHD. We previously reported decreased cerebral blood flow in the right lateral prefrontal cortex and both orbitofrontal cortices in children with ADHD. Genetic investigations have shown that the α-2A-adrenergic receptor gene (ADRA2A) is associated with ADHD. Our aim was to examine whether the presence of a risk allele of the ADRA2A MspI polymorphism is associated with differences in regional cerebral blood flow in boys with ADHD. Methods: We recruited 21 Korean boys with ADHD (mean age 9.9, standard deviation [SD] 2.7 yr) and 11 age-and sex-matched controls (mean age 10.6 [SD 2.1] yr). Each participant underwent technetium-99m-hexamethylpropylene amine oxime ( 99m Tc-HMPAO) single-photon emission computed tomography. We performed image analyses with voxel-wise t statistics using SPM2. Results: We found regional hypoperfusion in the prefrontal regions, including the right orbitofrontal and right medial gyri, and the bilateral putamen and cerebellum in boys with ADHD relative to controls (p < 0.0005, uncorrected for multiple comparisons). Boys with ADHD who carried the C allele (n = 13) at the ADRA2A MspI polymorphism had reduced perfusion in the bilateral orbitofrontal regions compared with those without the C allele (n = 8) (p < 0.0005, uncorrected for multiple comparisons). Limitations: This study was limited by the small sample size, and we did not obtain genetic data from the controls. Conclusion: Our findings suggest that regional differences in cerebral perfusion in the orbitofrontal cortex represent an intermediate neuroimaging phenotype associated with the ADRA2A MspI polymorphism; these data support the validity of the noradrenergic hypothesis regarding the pathophysiology of ADHD.

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“…More recently, genetic studies have turned to genes associated with norepinephrine transmission. The norepinephrine synthetic enzyme dopamine beta hydroxylase (DBH) and the gene encoding for the a2A adrenoceptor have been associated with ADHD (Roman et al, 2003;Park et al, 2005). It should be noted that the D4 receptor has very high affinity for norepinephrine (Van Tol et al, 1991) and should really be considered a catecholamine receptor.…”

Section: Genetics Of Adhd: Focus On Catecholaminesmentioning

confidence: 99%

Stimulants: Therapeutic Actions in ADHD

Arnsten

2006

Neuropsychopharmacol

418

257

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Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating 'normal' individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well. Berridge et al have now shown that these low doses produce marked increases in norepinephrine and dopamine release in the prefrontal cortex, whereas having only subtle effects on subcortical catecholamine release. ihe prefrontal cortex regulates behavior and attention using representational knowledge, and imaging and neuropsychological studies have shown that the prefrontal cortex is weaker in subjects with ADHD. This cortical area is very sensitive to levels of catecholamines: moderate levels engage postsynaptic a2A-adrenoceptors and D1 receptors and improve prefrontal regulation of behavior and attention, while high levels impair prefrontal function via a1-adrenoceptors and excessive D1 receptor stimulation. Administering low doses of methylphenidate to rats improves the working memory and attentional functions of the prefrontal cortex, while high doses impair working memory and produce a perseverative pattern of errors similar to that seen in patients. The low dose improvement is hiocked by either an a2-adrenoceptor or Dl receptor antagonist, suggesting that both norepinephrine and dopamine contribute to the beneficial actions of stimulant medications.

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Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD

Cited by 82 publications

References 41 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

Regional differences in cerebral perfusion associated with the α-2A-adrenergic receptor genotypes in attention deficit hyperactivity disorder

Stimulants: Therapeutic Actions in ADHD

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