Summary: A new investigation identifies a promising strategy to correct dopamine imbalances in the brain using a medication that blocks Kappa opioid receptors (Kor). In the mouse models with a rare mutation that makes dopamine filter, Kor blockers reduced this leak and restored normal behavior.
This approach could offer safer treatment alternatives for conditions such as ADHD, bipolar disorder and autism, which are often linked to interrupted dopamine signage. It is important to highlight that the treatment did not affect animals without mutation, which suggests a therapeutic potential directed with less side effects.
Key facts:
Directed action: Kor’s block reduces the leak of the dopamine transporter in mice with the DAT559 mutation. Behavior restoration: Kor blockers reversed cognitive and compulsive symptoms without affecting healthy animals. Implications: The results offer a new potential route to treat multiple brain disorders related to dopamines.
Source: Fau
Dopamine, a small molecule derived from amino acid tyrosine, plays an important role in regulating multiple essential brain functions that include 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 to accelerate or slow down the effects of dopamine. When dopamine is released from nerve cells, their efficient elimination to limit signaling occurs through special protein activity called “transporters”, ensuring a shorter action of dopamine in the brain.
Dopamine signaling interruptions have been related to several neuropsychiatric disorders, including ADHD, schizophrenia, bipolar disorder, autistic spectrum disorder, substance use disorder and addiction.
Current treatments for dopamine related conditions use agents that can block or improve dopamine signage, such as stimulants used to treat attention deficit disorder/hyperactivity, including amphetamines, which may have unwanted side effects or lead to addiction.
The power of dopamine to regulate the brain mechanisms of thought, mood and reward has kept scientists looking for better ways to control their actions.
In a recently published study in Molecular Magazine Psychiatry, Florida Atlantic University researchers and their collaborators have discovered a potentially safer but effective treatment for multiple disorders that show altered dopamine signaling. The “key?” A molecule that addresses a specific protein called Kappa opioid receptor (Kor).
Opioids are commonly known as powerful analgesics with strong psychoactive effects. They increase dopamine signage in the brain, producing pleasant sensations that can encourage repeated use and, over time, lead to addiction.
Endogenous and illegal opioid molecules act on signaling proteins called receptors. But all opioid receptors are not the same.
In the current study, the researchers attacked Kor, an opioid receptor subtype that when activated can reduce synaptic dopamine levels by decreasing dopamine release and increasing the availability of synaptic dopamine transporters, thus stopping the dopamine signal. Instead of activating Kor, scientists used a medication that can block it. But would this not cause addiction when raising dopamine?
“Everything depends on whether dopamine levels are elevated or suppressed by the insult produced by the disorder to begin with,” said Randy D. Blakely, Ph.D., principal author, executive director of the Fau Stiles-Nicholson Brain Institute, David Js Nicholson Distinguished Professor in Neuroscience and Professor of Biometic Science of Fau E. Schmidt College of Medicine.
“For some people, a rare genetic mutation known as DAT VAL559 makes the dopamine transporter
But shouldn’t a dopamine with leaks in the synapses raise dopamine in synapses and lead to addiction?
According to Blakely, unlike the strong increase in dopamine that triggers euphoria and can lead to addiction, dopamine that dribbles through a leak carrier makes it difficult for a receptive brain cell detecting the rapid normal increase in dopamine that acts to adjust our thought and emotions.
“The DAT559 genetic variant has been found in individuals with diagnoses of ADHD, ASD and BPD,” Blakely said. “This led us to reflect on whether the Kors blockade could reduce the expression of dopamine with leaks and, therefore, normalize the signaling of dopamine and restore normal cognition and behavior.”
The study results reveal that this is in fact the case. More than a decade ago, the Blakely team and collaborators showed that mice designed to express the mutation show altered behaviors that can be aligned with the characteristics observed in individuals with cognitive and compulsive disorders and responses of altered psychostimulants, curiously, in a sex dependent.
When the researchers administered a long -acting Kor blocking medication to these mice, they discovered that the agent reduced the expression of the mutant transporter on the cell surface where dopamine normally finds, preventing dopamine leaks from reaching dopamine receptors and correcting multiple behavior deficit observed in mutant mice.
“Our studies indicate that when there is a problem with how it is expressed, activated or inhibited, the brain may have altered the dopamine availability states, creating the features that psychiatrists describe as inactivity or compulsivity, as well as altered patterns of reactivity and reactivity,” said Felix P. Mayer, Ph.D., first author and former post-docker researcher in the Blakely laboratory of Blakely Blakely, a Laboratory of Felix, who is now the Cashsy member, the pH. De Copenhagen.
Mayer says that by blocking Kor, they have found a way to help solve this problem, at least in mice.
“Since the DAT mutation is rare, our findings could be considered of limited medical importance,” Blakely said.
“However, we and others have found that DAT proteins are regulated with multiple pathways within cells. Changes in any of these pathways, as well as changes that regulate how dopamine is released and act, could cause behavioral disorders that would benefit from Kor blockers.”
However, Blakely points out that antagonizing Kor could have opposite effects if the deregulation of dopamine signage is not the problem underlying diagnosis. The key will be to define the dopamine exchange rate that contributes to the disorder.
In particular, for the behaviors evaluated in the study, animals with normal DAT protein did not show behavioral changes when they were exposed to the Kor antagonist at the doses given, which suggests a certain degree of protection against side effects.
Researchers believe that additional work in Kor blockers can provide affected people with brain disorders that show these alterations better treatment options than those currently available today.
And although the DAT VAL559 mutation produces sexual behavioral changes dependent on the Kor, the Kor’s block improved the different alterations observed in men and women, which suggests that the usefulness of Kor’s blockers, at least in mice, is not limited by sex.
“The discovery of genetic variation in protein that strictly regulate Commonwealth.
The co-authors of the study 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., Faculty of Medicine and Health Sciences of the North Dakota University; Anthony W. Owens and Lynette C. Daws, Ph.D., Center for Health Sciences of the University of Texas in San Antonio; and Raajaram Gowrishankar, Ph.D.; Michelle Velez; Kyria Wickham; Hannah Phelps; Rania Katamish; and Maximilian Rabil, Fau Schmidt College of Medicine.
FINANCING: This work was supported by a Max Kade scholarship of the Academy of Sciences of Austria to Mayer, a subsidy of Young Narsad’s researcher from BBRF to Stewart, and the NIH P20 GM103442 Awards to Foster, P20 GM104360 to Vaughan, R01 MH093320 and R21 DA046044 to DAWS, R01 MH105050505050500 BLAKELY Y R01DA054694 A RAMAMOORTHY AND JAYANTHI.
On this neuroscience research news
Author: Gisele Galoustian
Source: Fau
Contact: Gisele Galoustian – Fau
Image: The image is accredited to Neuroscience News
Original research: open access.
“The antagonism of the Kappa opioid receptor restores phosphorylation, traffic and behavior induced by a variant of dopamine transporter associated with the disease” by Randy D. Blakely et al. Molecular psychiatry
Abstract
Kappa opioid receptor antagonism restores phosphorylation, traffic and behavior induced by a variant of dopamine transporter associated with the disease
The aberrant dopamine signaling (DA) is involved in schizophrenia, bipolar (BPD), autistic spectrum disorder (ASD), substance use disorder and attention deficit disorder of attention/hyperactivity (ADHD).
The treatment of these disorders remains inappropriate, as exemplified by the therapeutic use of D-Anhetamine and methylphenidate for the treatment of ADHD, agents with high responsibility for abuse.
In the search for an improved and non -addictive therapeutic approach to the treatment of disorders linked to DA, we use a preclinical mouse model that expresses the coding variant of the human day transporter () that encodes DAT559, previously identified in individuals with ADHD, ASD or BPD. DAT VAL559, like several other variants associated with DAT disease, exhibits an efflux gives anomalous (ADE) that can be blocked by D-Anfhetamine and methylphenidate.
Kappa opioid receptors (Kors) are expressed by means of neurons and modulate the release and clearance of DA, which suggests that Kors orientation could also provide an alternative approach to normalize the signaling gives interrupted by the DAT disturbed DAT function.
Here we demonstrate that Kor stimulation leads to greater surface traffic and phosphorylation of THR53 in DAT of wild type, effects achieved constitutively by the Mutant Val559.
In addition, these effects can be rescued by the Kor’s antagonism of DAT VAL559 in former Vivo preparations. It is important to highlight that Kor’s antagonism also corrected the in vivo of DA, as well as behavioral abnormalities dependent on sex observed in DAT Val55 mice.
Given its low responsibility for abuse, our studies with a construction of a valid model of human disorders associated with gives the considerations of Kor’s antagonism as a pharmacological strategy to treat brain disorders associated with DA.
