Recent studies indicate that it may be feasible to differentiate therapeutic effects from hallucinations in the development of new psychedelic medications. Research conducted on mouse models reveals that the anti-anxiety properties and the hallucination-inducing aspects of psychedelic drugs operate through separate neural pathways. This study was published on November 15 in Science.
The findings imply that isolating the positive effects of psychedelics from their hallucinatory effects is not solely dependent on chemical formulations, but rather depends on distinct neural circuitry.
“Previously, we relied on chemistry by creating new compounds, but this time we concentrated on pinpointing the circuits responsible for these effects, which appear to be distinct,” noted David E. Olson, co-author of the study and director of the Institute for Psychedelics and Neurotherapeutics (IPN) at the University of California, Davis. “This study provides significant mechanistic insights that validate our previous research.”
Assessing anti-anxiety behavior in mice
The researchers evaluated anxiety levels in mice using two primary experiments: the elevated plus maze and the marble burying test.
In the elevated plus maze, mice are positioned in a cross-shaped maze elevated a few feet off the ground. Two of the maze’s arms are enclosed with high walls, while the other two lack barriers. Mice exhibiting high anxiety typically prefer staying in the sheltered arms, avoiding exploration of the open sections.
During the marble burying test, anxious mice often engage in persistent and compulsive behavior by burying marbles within their bedding.
“It is widely recognized that psychedelics encourage reduced marble burying and foster exploration in the open arms of the elevated plus maze,” stated Christina Kim, the study’s lead author and assistant professor of neurology, who is closely associated with the Center for Neuroscience and IPN. “However, they also induce intoxicating or hallucinogenic effects, which can be detected through head twitches in mice.”
In this experiment, the research team administered the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) to the mouse models. They discovered that six hours post-dose, the mice exhibited less marble burying and more open arm exploration in the elevated plus maze, while the head twitches indicative of hallucinations had subsided.
“Our hypothesis was that if we could identify which neurons activated by DOI were linked to anxiety reduction, we might reactivate these neurons later to replicate those anti-anxiety-like results,” Kim explained.
To locate the specific neural circuits associated with the anti-anxiety effects, the researchers employed a molecular tagging technique known as scFLARE2, which highlighted neurons activated by DOI in the medial prefrontal cortex, a brain area recognized for its role in anxiety reduction in mice.
This tagging enabled the isolation of a psychedelic-responsive network distinct from the 5-HT2AR-expressing neurons, the main pathway through which psychedelics affect neuroplasticity.
Utilizing light to enhance anti-anxiety effects
With a fluorescent map of the neurons activated by DOI, the researchers applied optogenetics to reactivate these neurons.
“By utilizing scFLARE2 tagging and the subsequent reactivation of these specific prefrontal cortex cells, we were able to induce a reduction in anxiety-like behaviors, as indicated by decreased marble burying and heightened exploration of the open arms in the elevated plus maze,” Kim described. “We conducted this simply by targeting the DOI-activated cells and then reactivating them the following day.”
The research team further employed single nucleus RNA sequencing to genetically profile the specific types of neurons within the DOI-activated network. Among the nine neuron groups identified, three displayed significant activation.
“While some neuron types activated by DOI expressed high levels of 5-HT2AR, others did not,” Kim pointed out. “It’s likely that we are directly activating cells expressing 5-HT2AR, which then stimulate additional downstream cells, leading to behavioral changes.”
“It’s crucial to understand that the cells we are tagging and reactivating extend beyond just those expressing the drug’s receptor,” she emphasized.
This discovery highlights how activating certain brain nodes can have far-reaching effects throughout the broader neural network.
“Though DOI is a powerful psychedelic, it is not currently being investigated as a therapeutic agent in clinical settings. Therefore, the focus of this research is primarily on unraveling the basic circuit mechanisms of this significant class of drugs,” Kim expressed.
Clarifying how psychedelics influence brain function is a key objective for the IPN.
“Understanding which neural circuits are activated by psychedelics to produce their effects is fundamental science that will help in developing targeted therapies with enhanced safety profiles,” Olson stated.
Co-authors of the study include Jessie Muir, a postdoctoral researcher at the Center for Neuroscience, and Sophia Lin, a junior specialist at the same institution. Other contributors to the research include I.K. Aarrestad, H.R. Daniels, J. Ma, and L. Tian.
This research received support from several funding sources, including 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.
