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UMMS neuroscientists shed light on brain ‘braking’ mechanism associated with addiction, ADHD

New insights into dopamine transport may pave the way to different treatment approaches

By Sandra Gray

UMass Medical School Communications

November 30, 2015

Neuroscientists at UMass Medical School have discovered a molecular braking mechanism for the brain chemical dopamine that may lead to more effective treatments for some forms of attention deficit hyperactivity disorder (ADHD) and other mental health disorders in which abnormal dopamine function plays a central role.

“We identified the penultimate mechanism that controls dopamine transporter stability at the cell surface,” said Haley Melikian, PhD, associate professor of psychiatry at the UMMS Brudnick Neuropsychiatric Research Institute. “Our findings reveal a unique endocytic control switch that is highly specific for the dopamine transporter protein DAT. This switch can override a gene mutation found in a small subset of ADHD patients, which suggests that genetically manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct dysregulation.”

Dopamine is one of many neurotransmitters that carry signals between brain cells to control behavior and it is linked to both the rewards of stimulant drugs, including amphetamines and cocaine, and the over-stimulated behavior associated with ADHD. The amount of dopamine available to carry the signal is controlled by the specialized transport protein DAT, which acts like a vacuum to remove dopamine from around the brain cells and stop its signaling. In addition to its housekeeping functions, DAT is also the main target in the brain for abused stimulant drugs, such as cocaine and amphetamines, as well as therapeutic stimulants, such as Ritalin and Adderall, that are routinely used to treat ADHD. These drugs essentially plug up the vacuum cleaner, and cause dopamine to build up to excessive levels in the brain.

Dr. Melikian’s research focuses on how brain cells work to control DAT activity. A process called endocytic trafficking determines how much DAT is at the cell surface, where it needs to be situated to remove the excess dopamine surrounding the cells. The endocytic trafficking physically shuttles DAT from the cell surface to inside the cell, where it cannot work, and then back again. The Melikian lab previously identified a molecular mechanism called an “endocytic brake” that slows down this shuttling and stabilizes DAT on the cell surface. However, until their recent discovery, the machinery that controls this braking mechanism was completely unknown.

Sijia Wu, a doctoral candidate in Melikian’s lab and first author on the study, published in PNAS on Nov. 30, proved her hypothesis that the protein Ack1 is the switch that turns the endocytic braking mechanism on and off. Wu’s experiments showed that when Ack1 is activated and inactivated, whether by drugs or genetic manipulation, dopamine transporter availability at the cell surface increases and decreases.

The new understanding of Ack1’s role may have particular implications for some ADHD patients. Several mutant dopamine transporter gene mutations were recently discovered at Vanderbilt University by Randy Blakely, PhD, and Aurelio Galli, PhD. One of these mutations causes DAT to be highly unstable at the cell surface due to a loss of the endocytic brake.

“Since this mutant behaves as though it didn’t have a brake, we asked the question, if we could provide a brake that couldn’t be turned off, would that ‘rescue’ this ADHD DAT mutant?” recalled Melikian. “And indeed it did. When we imposed the irreversible brake onto that mutant, it restored normal dopamine transporter trafficking behavior.”

Further, the Ack1 braking mechanism is unique to DAT as it does not affect the transport proteins for other major neurotransmitters associated with mood and attention, such as serotonin, suggesting that DAT could be specifically targeted in a patient whose dopamine transporter had trafficking malfunction.

“Our finding that the nerves themselves have the capacity to change transporter function could lead to new ways to address abnormalities by using targeted gene therapies aimed at specialized intrinsic mechanisms that control dopamine function in the brain,” Melikian concluded.