The dopamine transporter (DAT) is a membrane transporter that clears DA from the synaptic cleft. This is also the main mechanism for clearance of released DA (50,51). DAT represents the major target for amphetamine and methylphenidate, the main pharmacological treatments for ADHD (52). DAT is expressed on presynaptic DA terminals, and can be used as specific marker for DA fibers.
An association between ADHD and polymorphisms in the DAT gene has been reported (53-55).
The DAT KO displays hyperactivity (56), which is likely to be owing to higher levels of brain DA, because of the absence of the clearance of DA from the synaptic cleft. Moreover, DAT KO mice reduce hyperactivity after treatment with psychostimulants, although they lack the DAergic target of psychostimulants. This suggest that psychostimulants, such as methylphenidate, could improve ADHD symptoms acting on non-DA sites, such as the serotonin (5 HT) system.
Behavioral analysis in the DAT KO is complicated by the growth-retardation phenotype
(57). In fact, these mice show anterior pituitary hypoplasia, dwarfism, lactation deficits, and high mortality (57).
Therefore, a mutant mouse with a decreased DAT level (knockdown) has been developed
(58). These mice express 10% of wild-type DAT levels (DAT knockdown), and are in a chronic state of hyper-DAergic activity. Moreover, they do not display the growth-retardation phenotype.
From the behavioral point of view, DAT knockdown mice have normal basal activity but become hyperactive in novel environments. Therefore, hyperactivity may be related to increased responses to novelty (59), decreased habituation (60-63), and higher motivational state.
It is still highly controversial whether ADHD is characterized by a hyper-DAergic or hypo-DAergic transmission (52). Consistent with the hyper-DA hypothesis, hyperactivity is usually related to a hyper-DAergic state (64,65). Furthermore, recent studies in ADHD patients have found a positive correlation between high DA metabolite homovanillic acid (HVA) levels and hyperactivity (66,67). DAT knockdown and KO mice (56) support the hyper-DA hypothesis.
The hypo-DAergic hypothesis of ADHD derives mainly from beneficial effects of psychostimulants (amphetamine and methylphenidate), which enhance DAergic transmission, in improving ADHD symptoms (52). However, DAT KO mice provide potential explanations for the calming effect of psychostimulants. In DAT KO mice, psychostimulant inhibition of locomotor activity is, in fact, mediated by an increased release of serotonin (56).
Moreover, all drugs (amphetamine, apomorphine, and quinpirole) that can activate DA D2 autoreceptors have a pronounced inhibitory effect on locomotor activity in DAT knockdown mice, whereas drugs that do not have an autoreceptor component (SKF-81297) have a less-pronounced stimulatory effect on locomotor activity. This suggests that the inhibitory effect of methylphenidate in ADHD may be the result of an altered balance between autoreceptor and heteroreceptor functions.
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