For some people, a rare genetic mutation known as DAT Val559 causes the dopamine transporter to “run backward,” leaking dopamine into the synapse rather than sucking it away, turning the transporter from an efficient nano-vacuum cleaner into a nano-leaky faucet.

Dopamine, a small molecule derived from the amino acid tyrosine, plays a significant role in regulating multiple essential brain functions including movement, mood and motivation as well as multiple cognitive functions including attention and memory. Dopamine signaling in the brain is a complex process, with many mechanisms in place to accelerate or slow down dopamine’s effects. When dopamine is released from nerve cells, its efficient removal to limit signaling occurs through the activity of special proteins called “transporters,” ensuring a shorter action of dopamine in the brain.

Disruptions in dopamine signaling have been linked to several neuropsychiatric disorders, including ADHD, schizophrenia, bipolar disorder, autism spectrum disorder, substance use disorder and addiction. Current treatments for dopamine-related conditions use agents that can either block or enhance dopamine signaling such as stimulants used to treat attention-deficit/ hyperactivity disorder including amphetamines, which can have unwanted side effects or lead to addiction. The power of dopamine to regulate brain mechanisms of thought, mood and reward has kept scientists searching for better ways to control its actions.

In a newly published study in the journal Molecular Psychiatry, researchers from Florida Atlantic University and their collaborators have discovered a potentially safer yet effective treatment for multiple disorders that display altered dopamine signaling. The “key?” A molecule that targets a specific protein called the kappa opioid receptor (KOR).

Opioids are commonly known as powerful painkillers with strong psychoactive effects. They increase dopamine signaling in the brain, producing pleasurable sensations that can encourage repeated use and, over time, lead to addiction. Both endogenous and illicit opioid molecules act on signaling proteins termed receptors. But all opioid receptors are not the same.

In the current study, the researchers targeted KOR, a subtype of opioid receptor that when activated can decrease synaptic dopamine levels by decreasing dopamine release and increasing the availability of synaptic dopamine transporters, thereby halting the dopamine signal. Instead of activating KOR, scientists used a drug that can block it. But wouldn’t this cause addiction by elevating dopamine?  

“It all depends on whether dopamine levels are elevated or suppressed by the insult that produces the disorder to begin with,” said Randy D. Blakely, Ph.D., senior author, executive director of the FAU Stiles-Nicholson Brain Institute, the David J.S. Nicholson Distinguished Professor in Neuroscience, and a professor of biomedical science in FAU’s Charles E. Schmidt College of Medicine. “For some people, a rare genetic mutation known as DAT Val559 causes the dopamine transporter to ‘run backward,’ leaking dopamine into the synapse rather than sucking it away, turning the transporter from an efficient nano-vacuum cleaner into a nano-leaky faucet.”

But shouldn’t a leaking dopamine into the synapses elevate dopamine in the synapse and lead to addiction? According to Blakely, unlike the sharp rise in dopamine that triggers euphoria and can lead to addiction, dopamine that dribbles out through a leaky transporter makes it hard for a receptive brain cell to detect the normal rapid rise in dopamine that acts to fine tune our thinking and emotions.

“The DAT Val559 genetic variant has been found in individuals with diagnoses of ADHD, ASD and BPD,” said Blakely. “This led us to ponder whether blocking KORs could reduce the expression of leaky dopamine transporters and thereby actually normalize dopamine signaling and restore normal cognition and behavior.”

Results of the study reveal that this is indeed the case. More than a decade ago, Blakely’s team and collaborators demonstrated that mice engineered to express the mutation show altered behaviors that can be aligned with features seen in individuals with cognitive and compulsive disorders and altered psychostimulant responses, interestingly, in a sex-dependent manner. 

When the researchers administered a long-acting KOR blocking drug to these mice, they found that the agent reduced the expression of the mutant transporter on the cell surface where it normally encounters dopamine, preventing dopamine leaks from reaching dopamine receptors and correcting multiple behavioral deficits seen in the mutant mice. 

“Our studies indicate that when there’s an issue with how DAT is expressed, activated or inhibited, the brain can have altered states of dopamine availability, creating the traits that psychiatrists describe as inattention or compulsivity as well as altered patterns of reactivity and emotion,” said Felix P. Mayer, Ph.D., first author and a former post-doctoral researcher in the Blakely lab, who is now a faculty member at the University of Copenhagen.

Mayer says that by blocking KOR, they have found a way to help fix this issue, at least in mice.

“Since the DAT mutation is rare, our findings might be considered of limited medical significance,” said Blakely. “However, we and others have found that DAT proteins are sensitively regulated by multiple pathways inside cells. Changes in any one of these pathways, as well as changes that regulate how dopamine is released and acts, could cause behavioral disorders that would benefit from KOR blockers.”

Blakely notes however that antagonizing KOR could have opposite effects if dysregulation of dopamine signaling is not the issue underlying the diagnosis. The key will be defining the type of dopamine change that contributes to the disorder. Notably, for the behaviors assessed in the study, animals with normal DAT protein failed to show behavioral changes when exposed to the KOR antagonist at the doses given, suggesting a degree of protection against side effects.

The researchers believe that further work on KOR blockers may give individuals affected with brain disorders that display these alterations better treatment options than what is currently available today. And although the DAT Val559 mutation produces sex-dependent behavioral changes, blocking KOR improved the distinct alterations seen in males and females, suggesting that utility of KOR blockers, at least in mice, is not limited by sex.

“The discovery of genetic variation in proteins that tightly regulate brain dopamine signaling, like DAT Val559, no matter how rare, can still offer insights into more common disease mechanisms,” said Sammanda Ramamoorthy, Ph.D., co-corresponding author on the study and a professor of pharmacology and toxicology at Virginia Commonwealth University.

Study co-authors are Adele Stewart, Ph.D., FAU Schmidt College of Medicine and Stiles-Nicholson Brain Institute; Durairaj Ragu Varman, Ph.D., and Lankupalle D. Jayanthi, Ph.D., Virginia Commonwealth University; Amy E. Moritz, Ph.D.; James D. Foster, Ph.D.; and Roxanne A. Vaughan, Ph.D., University of North Dakota School of Medicine and Health Sciences; Anthony W. Owens and Lynette C. Daws, Ph.D., University of Texas Health Science Center at San Antonio; and Raajaram Gowrishankar, Ph.D.; Michelle Velez; Kyria Wickham; Hannah Phelps; Rania Katamish; and Maximilian Rabil, FAU Schmidt College of Medicine. 

This work was supported by a Max Kade Fellowship of the Austrian Academy of Sciences to Mayer, a NARSAD Young Investigator Grant from the BBRF to Stewart, and NIH awards P20 GM103442 to Foster, P20 GM104360 to Vaughan, R01 MH093320 and R21 DA046044 to Daws, R01 MH105094 to Blakely and R01DA054694 to Ramamoorthy and Jayanthi.

-FAU-