A study by Duke researchers on the activity of a brain receptor in mice is providing new clues for treating obsessive behaviors in humans.
The researchers found that the overactivity of single chemical receptor—mGluR5, a neurological signalling receptor also found in humans—was associated with behaviors reminiscent of obsessive compulsive disorder. Their article was published in the journal Biological Psychiatry last month.
“These new findings are enormously hopeful for considering how to approach neurodevelopmental diseases and behavioral and thought disorders,” said Dr. Nicole Calakos, the study’s senior investigator and an associate professor of neurology and neurobiology at the Duke University Medical Center, in a Duke Today release.
In order to study how mGluR5 could cause these symptoms, the team deleted the Sapap3 gene—which organizes the connections between neurons so cells can communicate—in their mice. This led to an increase in mGluR5 activity. The researchers observed that these mice engaged in excessive grooming and displayed signs of anxiety.
When the mutated mice were given a molecule that reduced mGluR5 signalling, the mice quickly reduced their anxious behaviors.
Calakos told The Chronicle that the researchers also provided healthy mice with a molecule amplifying mGluR5 activity, which induced obsessive behaviors as well.
“One of the really cool things, in my opinion, was when we took an ordinary mouse and gave it a positive allosteric modulator, something which augmented the normal signaling of mGluR5,” Calakos said. “And the importance of that is that it’s a proof of principle [saying simply that] driving the activity of this receptor is sufficient to cause this biology.”
Calakos added that the effects of elevated mGluR5 activity led to irregularities in the mice’s straitum, a brain region which has been connected to OCD in humans.
“I think it’s very possible that this [pathway] is conserved between mice and humans, but it’s an experiment that needs to be done,” she said.
Obsessive compulsive disorder is defined by the National Institute of Mental Health as a “chronic and long-lasting disorder in which a person has uncontrollable, reoccurring thoughts (obsessions) and behaviors (compulsions) that he or she feels the urge to repeat over and over.”
Dr. Holly Rogers, a psychiatrist at Duke’s Counseling and Psychological Services, explained in an email that OCD can significantly disrupt the lives of afflicted individuals, something she sees often at Duke.
“Academically high-performing individuals tend to be fairly compulsive in my experience, so it is not surprising that we see OCD fairly often at CAPS,” she wrote.
Rogers noted that typical symptoms include compulsions to do certain behaviors, like checking locks repeatedly, counting steps, organizing desks a certain way or following a particular routine to leave the house.
“And they do these things so much that it interferes with their lives, like they can’t get to class on time or can’t get their work done because they spend so much time on the behaviors,” she wrote.
Although treatments such as selective serotitin reuptake inhibitors, or SSRIs, are common for treating OCD today, Dr. Rogers explained that this approach requires high doses over a long period of time and that symptoms often return after stopping medication.
Calakos noted that a 2007 study first demonstrated that removing Sapap3 in mice led to increased compulsive grooming behavior and partially modified their striatum circuitry, prompting her team to use Sapap3-lacking mice as models for studying OCD. In a later investigation in 2011, Calakos and her team found that deleting Sapap3 resulted in abnormal mGluR5 activity.
Until now, however, investigators had not made the direct connection between mGluR5 overactvity and OCD-like symptoms.
Going forward, Calakos said that although the behavioral consequences of mGluR5 overactivity could be different in humans compared to mice, her findings may still have implications in treating related anxiety conditions or specific subtypes of obsessive compulsive disorders, like trichotillomania, a hair-pulling disorder.
“Clinical trials can be difficult for diseases that have [diverse] causes,” she said. “It’s hopeful that if we can start identifying particular biological pathways and subgroups like mGluR5 overactive people, there may be a path forward to try certain drugs in those subgroups.”
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