Mar. 11, 2010 Although it's typically considered an adolescent curse, ADHD actually affects about five percent of adults as well. New research in a mouse model of attention deficit/hyperactivity disorder suggests that the root of the psychiatric disorder might be the over-activity of a protein that regulates dopaminergic pathways. The work suggests a path toward new treatments for symptoms including inattentiveness, over-activity and impulsivity.
The cause of ADHD is unknown, but there is increasing evidence that dopamine, a neurotransmitter involved in the brain's reward-motivation system, is involved. Scientists have found that the level of dopamine, and the D2 receptor it binds to, are involved in the progression of ADHD, as well as four connected regions in the frontal region of the brain, two of which are directly linked to reward and motivation.
The Rockefeller University researchers, led by Marc Flajolet, a senior research associate, and Paul Greengard, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience, focused on an enzyme called casein kinase I (CK1), which is involved in regulating the dopamine signaling pathway. The work was published in January in the Proceedings of the National Academy of Sciences.
Flajolet and coauthor Ming-Ming Zhou, a research associate in the lab, created a line of mice genetically modified to overexpress a form of CK1, called CK1δ, specifically in the forebrain of the mouse. Under normal conditions and in response to stimulation by drugs such as the ones used today to treat ADHD, the mice that overexpress CK1δ show behavioral symptoms and responses to drugs similar to those observed in people with ADHD.
"The genetically modified mice that we generated present interesting features such as hyperactivity and altered nesting capacities that might be related to attention deficit, and possibly altered impulsivity," says Flajolet.
To test the nesting capacities, the mice were kept overnight, singly housed in an open field arena, with pressed cotton nesting material. After 24 hours, the scientists compared the overall quality of the nests and the amount of material, if any, that each mouse used to build its nest. The normal mice tore up the pressed cotton and slept in the nests, while the CK1δ-overexpressing mice barely touched the cotton material.
The researchers also found that the CK1δ-overexpressing mice became less hyper in response to amphetamine and methylphenidate (Ritalin) in a way similar to that of ADHD patients. Finally, biochemical studies by Postdoctoral Associate Heike Rebholz showed that both classes of dopamine receptors, D1R and D2R, are significantly reduced in the CK1δ-overexpressing mice, further evidence that the dopaminergic system is severely affected.
"We believe that overexpression of CK1δ induces some developmental steps that resemble what might be happening in ADHD patients and therefore we propose that the CK1δ-overexpressing mice are a model for this disorder," says Flajolet. "It will be interesting to investigate if CK1 could be the origin of developmental defects in humans that lead to ADHD."
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- Zhou et al. Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.0915173107
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