Serotonin and the therapeutic effects of ritalin.

Gainetdinov et al. (1) reported that in dopamine transporter (DAT) knockout (KO) mice, which have elevated dopamine (DA) tone and are hyperactive, both psychostimulants and drugs that increase serotonin concentration in the brain decreased locomotor activity. They therefore suggested that the calming effects of psychostimulants in the DAT-KO mice are due to their ability to increase serotonin concentration, that the DAT-KO mouse may be a useful model for individuals with attentiondeficit hyperactivity disorder (ADHD), and that the so-called paradoxical calming effect of psychostimulants such as methylphenidate (Ritalin) in ADHD is due to their serotonergic effects. A central problem with this proposal is that unlike cocaine and amphetamine, methylphenidate does not increase the extracellular serotonin concentration in the brain (2). The affinity of methylphenidate for the serotonin transporter is very low (3), and if augmentation of serotonin did play an important role in the therapeutic effects of psychostimulants, one would expect serotonin transporter inhibitors to be beneficial in the treatment of ADHD, which they are not (4). Another problem with the interpretation is the very notion that the clinical effects of methylphenidate are paradoxical: children with ADHD respond to methylphenidate as nonaffected children do, as was shown some two decades ago (5). We question, too, whether the experimental results of Gainetdinov et al. are directly relevant to the therapeutic effects of methylphenidate. The methylphenidate doses given to the DAT-KO mice were more than three orders of magnitude higher than the doses given in the treatment of ADHD (30 mg/kg intraperitoneally in the mice versus 0.1 to 1 mg/kg orally in human patients). The temporal course of methylphenidate’s calming effects in the DAT-KO mice was very different from those of cocaine, amphetamine, or the serotonergic drugs. Whereas the latter drugs exerted an almost immediate calming effect, methylphenidate took more than 30 min to reduce locomotor activity in the DAT-KO mice and had its maximal calming effects 3 hours after its administration, a time at which the therapeutic effects of methylphenidate are dissipating in ADHD patients (6). The time of onset for methylphenidate’s locomotor effects in the wild-type animal, by contrast, was similar to those of cocaine and amphetamine. Hence, a pharmacokinetic explanation for the differences in the DAT-KO mice is unlikely; rather, those differences suggest that the calming effects of methylphenidate stem from a distinct mechanism relative to those of drugs that are known to increase serotonin concentration. In sum, linking the calming effects of serotonergic drugs in DAT-KO mice with the therapeutic effects of methylphenidate in ADHD patients may be unwarranted. There is no evidence that methylphenidate increases brain serotonin, nor is there evidence that pure serotonergic drugs are beneficial in ADHD. On the other hand, the work of Gainetdinov et al. in the DAT-KO mice clearly does confirm the important role of serotonin in modulating DA’s regulation of locomotor activity (7).