Anti-anxiety and hallucination-like effects of psychedelics mediated by distinct neural circuits
Mouse study suggests path to decouple benefits from hallucinogenic effects
University of California - Davis
image:
Working in a mouse model, UC Davis researchers are able to distnguish brain cells activated by a psychedelic drug. This image shows the prefrontal cortex of a mouse injected with scFLARE2 (purple) which drives the expression of a light-responsive channel in psychedelic-activated neurons (green or red). This allows researchers to visualize and artificially reactive these neurons at a later time point.
view moreCredit: Christina Kim, UC Davis
New research suggests that it could be possible to separate treatment from hallucinations when developing new drugs based on psychedelics. The anti-anxiety andhallucination-inducing qualities of psychedelic drugs work through different neural circuits, according to research using a mouse model. The work is published Nov. 15 in Science.
The research shows that decoupling the beneficial effects of psychedelics from their hallucinogenic effects isn’t just a matter of chemical compound design. It’s a matter of targeted neural circuitry.
“In the past, we did this using chemistry by making new compounds, but here we focused on identifying the circuits responsible for the effects, and it does seem that they are distinct,” said study co-author David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics (IPN) and a professor of chemistry and of biochemistry and molecular medicine at the University of California, Davis. “This is an important mechanistic study that validates our earlier results.”
Measuring anti-anxiety behaviors in mice
The researchers measured anxiety in mouse models with two tests: the elevated plus maze and the marble burying test.
In the elevated plus maze, mice are placed in a cross-shaped maze raised a couple of feet off the ground. Two arms of the maze have high walls while the other two arms remain open and have no walls. Mice with high anxiety tend to stay in the closed arms with high walls, not willing to explore the open arms.
In the marble burying test, mice with high anxiety tend to continuously and compulsively bury marbles in their bedding.
“It is well known that in mice, psychedelics induce reduced marble burying and promote exploration of the open arms of the plus maze,” said Christina Kim, the study’s corresponding author and an assistant professor of neurology, core member of the Center for Neuroscience and IPN affiliate. “But there is also an intoxicating or hallucinogenic-like effect, which can be measured through head twitches in mice.”
In the study, the team dosed mouse models with the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). They found that six hours after the dose, the mice still exhibited reduced marble burying and increased open arm time in the elevated plus maze. However, the head twitches associated with hallucinations had disappeared.
“We thought that if we could identify which neurons activated by DOI were responsible for reducing anxiety, then we might be able to reactivate them at a later time to mimic those anti-anxiety-like effects,” Kim said.
To identify the specific neural circuits associated with anti-anxiety effects, the team used a molecular tagging tool called scFLARE2 to highlight the neurons activated by DOI in the medial prefrontal cortex — a brain region known to be involved in reducing anxious behavior in mice.
The tagging allowed the team to isolate a psychedelic responsive network that extends beyond 5-HT2AR expressing neurons, the main receptor avenue through which psychedelics promote neuroplasticity.
Using light to promote anti-anxiety effects
Equipped with a fluorescent map of the neurons activated by DOI, the team then used optogenetics, or light, to reactivate those neurons.
“When we performed the scFLARE2 tagging and reactivation of these specific prefrontal cortex cells, we could still drive a reduction in anxiety-like behaviors, measured as decreased marble burying and increased open arm exploration in the elevated plus maze,” Kim said. “We could do this just by targeting the DOI-activated cells and then reactivating them the next day.”
The team also used single nucleus RNA sequencing to genetically profile the specific types of neurons in the DOI-activated network. Of the nine neuron group types identified, three exhibited high activation.
“While some of the cell types activated by DOI had strong 5-HT2AR expression, there were others that did not,” Kim said. “What is likely happening is that we are getting direct activation of cells that express 5-HT2AR, and then they go on to activate additional downstream cells that can trigger behavioral changes.”
“It is important to realize that the cells that we are tagging and reactivating extend beyond just those that express the receptor for the drug,” she added.
The finding emphasizes how activating single touchpoints in the brain spirals out into the rest of the network.
“While DOI is a potent psychedelic, it is not being explored as a potential therapeutic drug in the clinic. Thus the findings here are focused on dissecting the basic circuit mechanisms of this important class of drugs,” Kim said.
Elucidating exactly how psychedelics affect the brain is a major goal of the IPN.
“Understanding which neural circuits psychedelics activate to elicit their effects is the kind of basic science needed to ultimately develop targeted therapeutics with better safety profiles,” Olson said.
Co-authors Jessie Muir, a postdoctoral researcher at the Center for Neuroscience, and Sophia Lin, a junior specialist at the Center for Neuroscience, spearheaded the DOI study. Additional authors on the study include I.K. Aarrestad, H.R. Daniels, J. Ma and L. Tian.
Funding for the research was provided by the Burroughs Wellcome Fund Career Award at the Scientific Interface, the Brain & Behavior Research Foundation Young Investigator Award, the Searle Scholars Program, The Kavli Foundation, the UC Davis Behavioral Health Center for Excellence Pilot Award, the Canadian Institutes of Health Research postdoctoral training award, the National Institutes of Health, the Boone Family Foundation and the Camille Dreyfus Teacher-Scholar Award.
Journal
Science
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states
Article Publication Date
15-Nov-2024
COI Statement
David Olson is a cofounder of Delix Therapeutics, Inc., and serves as the chief innovation officer and head of the scientific advisory board. The remaining authors declare no other competing interests.
Study: How can low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviate symptoms within hours? UB research reveals how
University at Buffalo
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How can low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviate symptoms within hours? UB research reveals how
These images demonstrate the different binding sites in NMDA receptors that the UB team has discovered are responsible for ketamine’s distinct clinical effects, as an anesthetic at high doses and as an anti-depressant at very low doses. The image on the left shows ketamine bound in the central pore of the receptor, which results in anesthetic action; the one on the right shows ketamine bound in the lateral sites, which results in anti-depressive action.
view moreCredit: Jamie Abbott/University at Buffalo
BUFFALO, N.Y. — University at Buffalo neuroscientists have identified the binding site of low-dose ketamine, providing critical insight into how the medication, often described as a wonder drug, alleviates symptoms of major depression in as little as a few hours with effects lasting for several days.
Published in September in Molecular Psychiatry, the UB discovery will also help scientists identify how depression originates in the brain, and will stimulate research into using ketamine and ketamine-like drugs for other brain disorders.
PHOTOS: https://www.buffalo.edu/news/releases/2024/11/How-ketamine-lifts-depression-so-quickly.html
A lifesaving drug
Ketamine has been used since the 1960s as an anesthetic, but in 2000, the first trial of far lower doses of ketamine proved its rapid efficacy in treating major depression and suicidal ideation.
“Due to its fast and long-lasting effects, low-dose ketamine proved to be literally a lifesaving medicine,” says Gabriela K. Popescu, PhD, senior author on the research and professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB.
Traditional antidepressants take months to kick in, which increases the risk for some patients to act on suicidal thoughts during the initial period of treatment. Ketamine provides almost instant relief from depressive symptoms and remains effective for several days and up to a week after administration. Since this observation was published in the early 2000s, ketamine clinics, where the drug is administered intravenously to treat depression, have been established in cities nationwide.
But just how ketamine achieves such a dramatic antidepressive effect so quickly has been poorly understood at the molecular level. This information is critical to understanding not only how best to use ketamine, but also to developing similar drugs.
Selective effects on NMDA receptors
Ketamine binds to a class of neurotransmitter receptors called N-methyl-D-aspartate (NMDA) receptors. Popescu is an expert on how these receptors produce electrical signals that are essential for cognition, learning and memory, and how these signals, when dysregulated, result in psychiatric symptoms.
“We demonstrate in this article how ketamine at very low concentrations can affect the activity of only select populations of NMDA receptors,” says Popescu.
NMDA receptors are present throughout the brain and are essential for maintaining consciousness. For this reason, she explains, drugs that act indiscriminately on all NMDA receptors have unacceptable psychiatric side effects. “We believe that the selectivity we uncovered in our research explains how low-dose ketamine can treat major depression and prevent suicides in people with depression,” Popescu says.
The research was sparked by an observation in her lab by co-author Sheila Gupta, then a UB undergraduate. “Sheila noticed that when applied onto NMDA receptors that were chronically active, ketamine had a stronger inhibitory effect than expected based on the literature,” Popescu explains. “We were curious about this discrepancy.”
Back when ketamine’s antidepressant effects first became known, researchers tried to find out how it worked by applying it onto synaptic currents produced by NMDA receptors, but the drug produced little or no effect.
“This observation caused many experts to turn their attention to receptors located outside synapses, which might be mediating ketamine’s antidepressive effects,” Popescu says. “Sheila’s observation that ketamine is a stronger inhibitor of receptors that are active for longer durations inspired us to look for mechanisms other than the direct current block, which was assumed to be the only effect of ketamine on NMDA receptors.”
Few labs with this NMDA expertise
Popescu’s lab is among a handful in the world with the expertise to quantify the process by which NMDA receptors become active. This allowed Popescu and her colleagues to identify and measure what exactly changed during the NMDA activations when ketamine was present at very low doses versus when it was present at high (anesthetic) doses.
“Because we track activity from a single receptor molecule over an extended period of time, we can chart the entire behavioral repertoire of each receptor and can identify which part of the process is altered when the receptor binds a drug or when it harbors a mutation,” Popescu explains.
“The mechanism we uncovered suggests that at low doses, ketamine will only affect the current carried by receptors that had been active in the background for a while, but not by synaptic receptors, which experience only brief, intermittent activations,” she continues. “This results in an immediate increase in excitatory transmission, which in turn lifts depressive symptoms. Moreover, the increase in excitation initiates the formation of new or stronger synapses, which serve to maintain higher excitatory levels even after ketamine has cleared from the body, thus accounting for the long-term relief observed in patients.”
The UB research helps explain why such low doses of ketamine are effective.
“Our results show that very low levels of ketamine, on the nanoscale, are sufficient to fill two lateral grooves of the NMDA receptors to selectively slow down extra-synaptic receptors, alleviating depression. Increasing the dose causes ketamine to spill over from the grooves into the pore and begin to block synaptic currents, initiating the anesthetic effect.” says Popescu.
Popescu’s co-authors in the Department of Physics in the College of Arts and Sciences simulated the three-dimensional structure of the NMDA receptor and predicted the exact residues to which ketamine binds in the lateral sites. “These interactions are strong and account for the high affinity of the receptor for low doses of ketamine,” she says.
“The simulations show that at high concentrations, which is how it is used as an anesthetic, ketamine indeed lodges itself in the central ion-conducting pore of the receptors, where it stops ionic current from flowing through the receptor,” says Popescu.
In contrast, at low concentrations, ketamine functions very differently, attaching to two symmetrical sites on the sides of the pore, such that instead of stopping the current, ketamine makes receptors slower to open, reducing the current only a little bit. “Finding the exact binding site on the receptor offers the perfect template for developing ketamine-like drugs that could be administered orally and may lack the addictive potential of ketamine,” says Popescu.
The natural next step is to screen existing drugs that can fit in the lateral grooves of NMDA receptors, first computationally and then experimentally.
Lead authors are Jamie A. Abbott, PhD, in the Department of Biochemistry, and Han Wen in the Department of Physics. Other co-authors are Gupta, Wenjun Zheng Beiying Liu and Gary J. Iacobucci. The research was funded by the National Institutes of Health.
Journal
Molecular Psychiatry
Method of Research
Experimental study
Subject of Research
Human tissue samples
Article Title
Allosteric inhibition of NMDA receptors by low dose ketamine
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