American scientists have discovered how methylphenidate (Ritalin), which is often given to calm children with attention deficit hyperactivity disorder (ADHD), works in an animal model of the condition. Their work may solve the riddle of why psychostimulants are useful in treating ADHD.
Methylphenidate is often prescribed to children who engage in hyperactive behaviour as part of ADHD. The drug seems to reduce hyperactivity in these children and improve their cognitive performance, but there has been little knowledge about its mode of action.
A research team from Duke University in North Carolina has found that the hyperactivity symptoms of ADHD are probably caused by children having too little serotonin in addition to high concentrations of dopamine. Drugs such as methylphenidate work by restoring the balance between serotonin and dopamine in the brain (Science 1999;283:397-401). “Since we know that the symptoms of ADHD mostly resolve in adolescents, this may be because the neurotransmitter system matures, resulting in a better balance between serotonin and dopamine,” suggested Marc Caron, a member of the research team.
The findings have come from research on a genetically modified mouse in which the dopamine transporter gene was eliminated, leading to high concentrations of extracellular dopamine. These mice have been found to behave in much the same way as hyperactive children. “They were hyper, impulsive, and had an inattentive manner,” reported Dr Caron.
Dr Caron and his colleagues administered methylphenidate and amphetamines to normal mice and to the genetically modified mice. The normal mice became agitated and showed an increase in dopamine concentrations, but the modified mice calmed down, and there was no change in their extracellular dopamine concentrations.
These observations led Dr Caron to deduce that methylphenidate does not act directly on the dopamine system. The team used a compound which directly blocks the noradrenaline transporter protein and found that this compound had no effect on the hyperactive mice. Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, seemed to mimic the action of methylphenidate in the modified mice. The researchers confirmed that the serotonin system was implicated by administering a direct serotonin receptor agonist that mimicked methylphenidate.