Neuropsychopharmacology: The Fifth Generation of Progress
not in other studies (124,138). In the study by Waldman et al. (137), hyperactive-impulsive symptoms but not inatten- tive symptoms were related to the number of DAT high- risk alleles. Further support for a link between the DAT gene and ADHD comes from a study that relates this gene to poor methylphenidate response in children with ADHD (139) and from the neuroimaging study (Table 43.2) show- ing that DAT activity in the striatum is elevated by 70% in adults with ADHD (67).
In mice, eliminating DAT gene function leads to several features suggestive of ADHD: hyperactivity, deficits in in- hibitory behavior, and a paradoxical response to stimulants (i.e., stimulants reduce hyperactivity) (37,140). Studies of this knockout mouse model show the potential complexities of gene–disease associations. The loss of the DAT gene has many biological effects: increased extracellular dopamine, a doubling of the rate of dopamine synthesis (141), decreased dopamine and tyrosine hydoxylase in striatum (142), and a nearly complete loss of functioning of dopamine autore- ceptors (143). Because ADHD is believed to be a hypodopa- minergic disorder, the decreased striatal dopamine may be most relevant to the disorder.
Gainetdinov et al. showed that enhancement of seroto- nergic transmission mediates the mouse’s paradoxical re- sponse to stimulants (37). These researchers attributed this to the effects of stimulants on the serotonin transporter. To complicate matters further, Bezard et al. showed that DAT knockout mice did not experience MPTP-induced dopami- nergic cell death (144), and another study found a gradient effect such that mice with zero, one, and two functional DAT genes showed increasing susceptibility to MPTP (145). These latter findings suggest that individual differ- ences in the DAT gene may mediate susceptibility to neuro- toxins having an affinity for the DAT.
A population-based association study has also implicated the A1 allele of the dopamine D2 receptor gene in ADHD (146). Absence of the D2 gene in mice leads to significantly reduced spontaneous movements, a finding suggesting that D2 plays a role in the regulation of activity levels (147, 148). Mice without D2 genes also show decreased striatal DAT functioning (149), a finding that illustrates the poten- tial effects of gene–gene interaction on simple phenotypes such as locomotion in mice. In addition, Calabresi et al. used the D2 knockout mouse to study the role of the D2 receptor in striatal synaptic plasticity (150). In these mice, these researchers found abnormal synaptic plasticity at corti- costriatal synapses and long-term changes in synaptic effi- cacy in the striatum.
The only human study of the D3 receptor gene found no evidence of an association with ADHD (151). However, homozygous mice lacking D3 receptors displayed increased locomotor activity, and heterozygous mice showed less pro- nounced hyperactivity. These results led Accili et al. to con- clude that D3 receptors play an inhibitory role in the control of certain behaviors (152).
Four human studies of ADHD have examined the cate- chol-O-methyltransferase (COMT) gene, the product of which is involved in the breakdown of dopamine and norep- inephrine. Although one study found that ADHD was asso- ciated with the Val allele (153), others have found no associ- ation between the COMT polymorphism and ADHD in Irish (154), Turkish (155), and Canadian (156) samples. Despite the negative finding, the positive finding is intrigu- ing because the Val allele leads to high COMT activity and an increased breakdown of catecholamines.
Another study found an association with the DXS7 locus of the X chromosome, a marker for monoamine oxidase that encode enzymes that metabolize dopamine and other neurotransmitters (157). Finally, Comings and colleagues found associations and additive effects of polymorphisms at three noradrenergic genes (the adrenergic 2A, adrenergic
2C, and dopamine--hydroxylas) on ADHD symptoms in
a sample of patients with Tourette syndrome (158), but they found no association between the tyrosine hydroxylase gene and ADHD in this sample (159).
Some investigators have used the coloboma mouse model to investigate the genetics of ADHD. These mice have the coloboma mutation, a hemizygous, 2-centimorgan deletion of a segment on chromosome 2q. The mutation leads to spontaneous hyperactivity (which is reversed by stimulants), delays in achieving complex neonatal motor abilities, defi- cits in hippocampal physiology that may contribute to
learning deficiencies, and deficits in Ca2 mine release in dorsal striatum (160).
The coloboma deletion region includes the gene encod- ing SNAP-25, a neuron-specific protein implicated in exo- cytotic neurotransmitter release. Hess et al. suggested that interference with SNAP-25 may mediate the mouse’s hyper- activity (161). As predicted by this hypothesis, when these investigators bred a SNAP-25 transgene into coloboma mice, the animals’ hyperactivity was reduced. Moreover, other work suggested that reduced SNAP-25 expression leads to striatal dopamine and serotonin deficiencies, which may be involved in hyperactivity (162).
Hess et al. tested the idea that the human homologue of the mouse coloboma gene could be responsible for ADHD by completing linkage studies of families with ADHD by using markers on human chromosome 20p11- p12, which is syntenic to the coloboma deletion region (111). These investigators used five families for which segre- gation analysis suggested that ADHD was the result of a sex-influenced, single gene. However, no significant linkage was detected between ADHD and markers on chromosome 20p11-p12.
ENVIRONMENTAL RISK FACTORS
Although genetic studies of ADHD unequivocally show that genes are risk factors for the disorder, they also show