Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder

154

Section: Drd4 Vntr In Attention Deficit Hyperactivity Disorder (Adhd)mentioning

confidence: 95%

Section: Statistical Considerationsmentioning

confidence: 99%

Dopamine D4 Receptor Gene Novelty or Nonsense?

Paterson

Sunohara

Kennedy

1999

154

“…Furthermore, the 7 repeat allele of DRD4 mediates a blunted response to dopamine (Ashgari et al 1995). To date, there have been 16 studies examining for association between the 7 repeat DRD4 polymorphism and ADHD, with positive results in many (LaHoste et al 1996;Swanson et al 1998b;Smalley et al 1998;Rowe et al 1998;Faraone et al 1999;Muglia et al 2000;Holmes et al 2000;Sunohara et al 2000;Tahir et al 2000a;Mill et al 2001), but not all (Castellanos et al 1998; Comings et al 1999;Eisenberg et al 2000;Hawi et al 2000a;Kotler et al 2000;Todd et al 2001) studies. A recent meta-analysis of DRD4 by Faraone et al 2001 supported an overall association (albeit small) between DRD4 and ADHD.…”

Section: Converging Evidence Has Implicated Abnormalities Of Dopaminementioning

confidence: 99%

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

Kirley

Hawi

Daly

et al. 2002

106

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD).Attention Deficit Hyperactivity Disorder (ADHD) is a common condition of childhood affecting 3-6% of school age children worldwide (Barkley 1990), with males being affected three times more than females (Anderson et al. 1987; Baumgartel et al. 1995). Its core clinical features include excessive motor activity, impaired attention, and impulsivity. ADHD causes marked educational, social, and family difficulties for sufferers and their relatives. The condition is of early onset (usually before age 7) and tends to persist throughout childhood. Moreover, approximately 30-60% of children with ADHD have persisting psychopathology in adulthood (Gittelman et al. 1985;Weiss and Hechtman 1986; Barkley 1990;Swanson et al. 1998a). The exact etiology of ADHD is Received March 8, 2001; revised February 12, 2002; accepted February 20, 2002. Online publication: 2/28/02 at www.acnp.org/citations/ Npp022802254. 608 A. Kirley et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 unknown, but a substantial genetic element exists. This has been demonstrated by family (Biederman et al. 1990(Biederman et al. , 1992Faraone et al., 1992Faraone et al., , 1994, twin (Thapar et al. 1995;Silberg et al. 1996;Levy et al. 1997), and adoption studies (Alberts-Corush et al. 1986; Cadoret and Stewart 1991). The heritability (h 2 ) of ADHD has been estimated to be .50-.98 (Gjone et al. 1996;Levy et al. 1997). The exact mode of transmission remains unknown. Segregation analyses (Morrison and Steward 1974;Deutsch et al. 1990, Faraone et al. 1992, Hess et al. 1995 have proposed models of inheritance from major gene effects through oligogenic to polygenic and multifactorial models, but the differences in statistical "fit" between multifactorial genetic models and single gene inheritance is modest. The multifactorial concept is consistent with ADHD's high population prevalence (2-7%), high concordance in monozygotic twins (68-81%), but modest recurrence risks to first-degree relatives.Dysregulation in catecholamine neurotransmission is implicated in the pathophysiology of ADHD (Faraone and Biederman 2002). The dopaminergic neurotransmitter system has been most extensively studied. This article will focus mainly on its role in the etiology of ADHD. Evidence to support dopaminergic dysfunction in ADHD derives from three research areas: the neuropharmacology of stimulant medication (Zametkin and Rapoport 1987; Amara and Kuhar 1993), the behavior and biochemistry of animal models (Giros et al. 1996;Gainetdinov et al. 1999, Russell 2000, and neuroimaging studies in ADHD adults (Dougherty et al. 1999, Krause et al. 2000, and Faraone and Biederman 2002. For this reason, many molecular genetic studies have focused on dopamine system genes.The gene encoding the dopamine transporter, DAT1, was the initial candidate gene studied. This gene is of particular interest, as the transporter is the principal target...

Section: Genetic Studies Suggest That Dopamine D 4 Receptor Polymorphmentioning

confidence: 99%

“…One such allele is the D 4.7 receptor, containing seven repeats of this sequence. It has repeatedly been associated with ADHD, as well as related behavioral traits such as novelty-seeking and impulsivity (Benjamin et al 1996;Ebstein et al 1996;La Hoste et al 1996;Bailey et al 1997;Rowe et al 1998;Swanson et al 1998;Faraone et al 1999;Barr et al 2000).Some features of ADHD are simulated in several laboratory models, including: (1) rats with neonatal lesions of the central DA system induced by the neurotoxin 6-hydroxydopamine (6-OHDA; Shaywitz et al 1976); (2) the spontaneously hypertensive Kyoto-Wistar rat (Tucker and Johnson 1981); (3) nonhuman primates treated with the DA neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Roeltgen and Schneider 1991); and (4) genetic knock-out mice lacking functional DAT (Giros et al 1996). Juvenile male rats with neonatal 6-OHDA lesions are a particularly appropriate model for the hyperactivity of ADHD in that lesion-induced motor hyperactivity is most prominent at an age corresponding to human periadolescence (Shaywitz et al 1976;Erinoff et al 1979), and is dose-dependently antagonized by stimulants used to treat clinical ADHD (Heffner and Seiden 1982).…”

mentioning

confidence: 99%

Plasticity of Dopamine D4 Receptors in Rat Forebrain Temporal Association with Motor Hyperactivity Following Neonatal 6-Hydroxydopamine Lesioning

Zhang

Tarazi

Davids

et al. 2002

Genetic studies suggest that dopamine D 4 receptor polymorphism is associated with attention deficit hyperactivity disorder (ADHD). We recently reported that motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine lesions of the central dopamine system canAttention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition characterized by hyperactivity, inattention and impulsivity, typically in school-aged boys (Barkley 1990). Abnormal dopamine (DA) neurotransmission has long been considered to underlie the disorder since most symptoms of ADHD can be alleviated by psychostimulant drugs, notably methylphenidate and amphetamines, that release DA among other actions. Increased radioligand binding to dopamine transporters (DAT) in patients with ADHD identified in recent brain imaging studies further implicates deficient DA functioning in the disorder (Dougherty et al. 1999;Dresel et al. 2000).DA modulates physiological processes through activation of five G-protein NO . 5 ADHD by genetic linkage studies (La Hoste et al. 1996). Human D 4 receptors occur in multiple forms with 2-11 copies of a 16-amino acid sequence in the putative third intracellular loop of the peptide (Van Tol et al. 1992;Lichter et al. 1993;Asghari et al. 1994). One such allele is the D 4.7 receptor, containing seven repeats of this sequence. It has repeatedly been associated with ADHD, as well as related behavioral traits such as novelty-seeking and impulsivity (Benjamin et al. 1996;Ebstein et al. 1996;La Hoste et al. 1996;Bailey et al. 1997;Rowe et al. 1998;Swanson et al. 1998;Faraone et al. 1999;Barr et al. 2000).Some features of ADHD are simulated in several laboratory models, including: (1) rats with neonatal lesions of the central DA system induced by the neurotoxin 6-hydroxydopamine (6-OHDA; Shaywitz et al. 1976); (2) the spontaneously hypertensive Kyoto-Wistar rat (Tucker and Johnson 1981); (3) nonhuman primates treated with the DA neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Roeltgen and Schneider 1991); and (4) genetic knock-out mice lacking functional DAT (Giros et al. 1996). Juvenile male rats with neonatal 6-OHDA lesions are a particularly appropriate model for the hyperactivity of ADHD in that lesion-induced motor hyperactivity is most prominent at an age corresponding to human periadolescence (Shaywitz et al. 1976;Erinoff et al. 1979), and is dose-dependently antagonized by stimulants used to treat clinical ADHD (Heffner and Seiden 1982). In addition, the model is associated with learning deficits that are also antagonized by stimulants (Takasuna and Iwasaki 1996;Wool et al. 1987).We found recently that motor hyperactivity following 6-OHDA lesioning of neonatal rats can be reversed dose-dependently by selective antagonists for D 4 but not D 2 receptors, and exacerbated by a D 4 agonist (Zhang et al. 2001b). In addition, motor hyperactivity correlated closely with the magnitude of increased D 4 , but not D 2 receptor binding in basal forebrain. The present study further inv...