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 Research & Giving News Article  This is the significance of new research performed by a NARSAD Distinguished Investigator and colleagues at Vanderbilt University, and reported last week in the Journal of Neuroscience. ADHD is one of the most common mental health disorders in children and adolescents, affecting up to 5 percent of school-age children in the United States. Randy Blakely, Ph.D., who was named a Distinguished Investigator by NARSAD in 2005 and serves on NARSAD’s Scientific Council, led a team whose study centered on a gene on human chromosome 5 that instructs certain cells to generate so-called dopamine transporter molecules. Dopamine transporters are relatively large protein molecules embedded in the membranes of nerve cells that enable them to “dock” with vital neurotransmitting molecules called dopamine. A particular defect in the gene that directs production of the dopamine transporter -- a variation of only one “letter” of the genetic code -- was found in two brothers, both of whom have ADHD. This variation caused the transporter to malfunction: it behaved in the manner that normal transporter molecules behave when amphetamine, or “speed,” is present. The finding supports the thesis of an association between this genetic variation, the anomaly in dopamine transporter function the team noted, and the presence of ADHD in these particular individuals. “We believe that this is important evidence that ADHD can be caused by a functional deficit in the brain's dopamine signaling pathway,” said Dr. Blakely, who is a professor and director of the Center for Molecular Neuroscience at Vanderbilt University. What the dopamine transporter is supposed to do The dopamine transporter, when present, not only enables nerve cells to bind dopamine; it also contains the machinery through which dopamine is cleared from the gap between adjacent nerve cells, called synapses. In healthy people, this clearing of the neurotransmitter occurs at characteristic intervals following the successful propagation of nerve signals. Scientists hypothesize that various malfunctions in the dopamine transporter are involved in disorders including attention-deficit hyperactivity disorder (ADHD), depression, bipolar disorder and schizophrenia. Gene variant makes the transporter “run backward” Dr. Blakely and colleagues say that the gene variant in the brothers produces transporters that appear to “run backward”: the transporter pushes dopamine out into the space between neurons -- like normal transporters do when amphetamine is present -- altering dopamine signaling and contributing, they believe, to the symptoms of ADHD. The children with the genetic variation behave as if they were “on amphetamine all the time,” said Aurelio Galli, Ph.D., an investigator in the Center. Amphetamine causes hyperactivity, paranoia and psychosis in healthy people. Variations in brain dopamine signaling have long been suspected to participate in the development of ADHD and other neuropsychiatric disorders. Dopamine has roles in brain circuits linked to attention, motor function, reward and cognition. Drugs that target dopamine transporters and receptors are used to treat ADHD, bipolar disorder and schizophrenia. The particular mutation at the focus of this study was reported at least once before in a patient with bipolar disorder. That disease also has connections to dopamine signaling, but the functional impact of the mutation had not been established, according to Dr. Blakely. “Listening in” on individual neurons In initial studies of the variant transporter in cultured cells, the group found no differences in function compared to the normal transporter -- the mutant transporter moved dopamine into the cell and was appropriately regulated by dopamine transporter blockers and cellular signaling pathways. Turning to a sensitive technology called amperometry that uses a small carbon fiber to “listen in” on how single cells release or transport dopamine, the Galli and Blakely laboratories discovered that the altered transporters were running backward at an exaggerated rate, literally pushing dopamine out of the cell. “We think this activity would short-circuit the normal synaptic transmission process,” Dr. Blakely said. “Instead of the precise 'pop-pop-pop' of dopamine being released from vesicles (tiny packets of neurotransmitter), there's a cloud of dopamine bleeding out, and the dopamine signaling system is not as sharp as it should be.” To their surprise, the investigators also found that amphetamine blocks the leak of dopamine through variant transporters. Normally, amphetamine does just what the mutation does -- it causes the dopamine transporter to run in the reverse direction. Drug conundrum explained? The findings offer a new perspective on a conundrum in the ADHD field -- the fact that two of the medications that successfully treat the disease have opposing effects on their molecular target, the dopamine transporter. With the normal dopamine transporter, methylphenidate (Ritalin) blocks the ability of amphetamine (Adderall) to make the transporter run backward, yet both drugs are equally beneficial to patients with ADHD. But when the transporter runs backward of its own accord, as it does with this rare mutant version, both agents act as blockers and stop the leak of dopamine. “This observation unifies the action of these drugs and strongly suggests that backward-running transporters may be an important mechanism in ADHD, even for those who do not have this particular mutation,” Dr. Blakely said. This article was adapted by NARSAD with permission of Vanderbilt University. |
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