Medicine enhance serotonin, socialization in a number of autism mouse fashions | Spectrum
Friend Zone: Mice with autism-related mutations overcome their disinterest in other mice after receiving MDMA or an experimental serotonin agonist.
Stuart Wilson / Science Source
Two unapproved drugs that increase the neurotransmitter serotonin significantly increase sociability in six autism mouse models, according to a new study.
The findings build on decades of work suggesting that the release of serotonin in the nucleus accumbens, part of the brain’s social reward system, is important for social interactions and promoting sociability, says lead researcher Robert Malenka, professor of Psychiatry and Behavioral Science from Stanford University in California. Artificially stimulating serotonin release in the nucleus accumbens in mice with an autism-related mutation reduces their reluctance to socialize with other mice, a 2018 study by Malenka’s team showed.
In the new work, the team used MDMA, also known as ecstasy, and an experimental serotonin agonist called CP-94,253 to stimulate serotonin switching in mouse models of multiple autism. Both drugs brought the animals’ interest in socialization back to a level close to that of their wild-type counterparts.
“I really didn’t expect that,” says Malenka. “I thought it might work on one or two models, but not the other. But we kept doing model by model, and it kept working. ”Malenka is the founder and Scientific Advisory Board member of Maplight Therapeutics, a biotech company recruiting participants in a Phase II study of another serotonin agonist for autism.
The results could lead to drugs to alleviate social difficulties in people with autism, say the researchers, although other experts caution.
A first step is to assess whether these drugs really increase social function in mice, because the behavior tests used here only measured narrow dimensions of socialization, says Jeremy Veenstra-VanderWeele, professor of psychiatry at Columbia University, who is not involved in the study was involved. “These tests are geared towards social interest or engagement. Many autistic people are very interested in other people but still have social problems, and a drug that increases social interest may not help them. “
Orientation towards sociability:
In the new study, Malenka and his colleagues tested every drug on mice with a mutation in chromosomal region 16p11.2 or in the CNTNAP2 or FMR1 genes, all of which have been linked to autism. They also tested the drugs on mice exposed in the womb to the epilepsy drug valproic acid, which has been linked to autism. They also tested CP-94.253 on mice with mutations in the ACTL6B or ARID1B genes, both of which are linked to autism.
The team chose these models in part because each involves a different biological pathway but exhibits the same behavior – a reluctance to socialize compared to wild-type mice. The paper appeared in Neuropsychopharmacology on July 8th.
The two drugs in the study have different mechanisms and are also different from the class of drugs known as selective serotonin reuptake inhibitors (SSRIs), which can treat concurrent conditions like depression and anxiety, but which do not appear to affect the core characteristics of autism . While CP-94,253 activates a number of serotonin receptors, MDMA stimulates the release of serotonin. SSRIs, on the other hand, slow the rate at which serotonin is recycled.
All three increase serotonin levels, but CP-94.253 and MDMA do so within minutes or hours, while SSRIs work within weeks.
Clinical Value:
The range of mouse models that responded to the study drugs supports the idea that different genetic mutations associated with autism can converge in the same pathways and that treating these pathways improves human functioning, says Elizabeth Berry-Kravis, professor of child neurology at Rush University Medical Center in Chicago, Illinois, who was not involved in this work. “It’s nice to see some support for this concept.”
But previous drug studies have shown great promise in mice and then haven’t produced similar results in humans, she says. “I’ve become a very sane skeptic about things that fix the mouse.”
Future clinical trials should test the potential drugs on people screened to see the greatest response, she says. Screening could ensure that participants share a genetic marker, brainwave signature, or social trait that unite the group and give researchers something to measure to see an effect.
This subtyping is great in theory, says Malenka. “In practice, especially for a small biotech, that’s basically impossible.”
There are now serotonin agonists approved for humans. For example, triptans, which are commonly used to treat or prevent migraines, appear to be relatively safe in people. Hence, the idea that this class of drugs could have potential for autism is exciting, says Veenstra-VanderWeele.
“To the best of my knowledge, people taking these drugs do not report increased social engagement,” he says, “but they usually take these drugs for debilitating headaches, so social engagement may not be the primary concern.”
Quote this article: https://doi.org/10.53053/LQZH6060
