Summary: New analysis has identified different neurological circuits for the anti-anxiety and psychedelic effects of opiates. Researchers found that stress reduction persists well after hallucinogenic effects have faded by using the psychedelic DOI in mice.
They identified distinct prefrontal brain cells that provide anxiety relief by tracking activated head cells with chemical naming and reactivating them with light.
The results suggest it may be possible to develop psychedelics-based solutions that reduce anxiety without producing illusions. This study also highlights the complexity of direct and indirect neural networks, both river and upstream.
Important Facts:
- After illusions are over, opiates still have anti-anxiety effects.
- Direct and river detection occurs in neural circuits used to relieve stress.
- Neuroscience reactivated anxiety-reducing cells freely of drugs.
Origin: UC Davis
When developing innovative stimulants based on psychedelics, new research suggests that it might be possible to distinguish between hallucinations and care. The anti-anxiety andhallucination-inducing elements of psychedelic drugs work through various neurological wires, according to studies using a keyboard design.  ,
The job is published Nov. 15 in , Science.  ,
The findings of the study demonstrate that the design of chemical compounds does n’t just affect how well psychedelics work. It’s a matter of qualified neurological 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” . ,
Evaluating anti-anxiety actions in animals
The raised and labyrinth and the stone burying test were used by the researchers to assess the level of anxiety in mouse models.  ,
Mice are raised a few feet above the ground in the increased plus labyrinth, which is a cross-shaped maze. The maze’s two empty hands have no walls, while the other two have substantial walls. High-anxiety patients are more likely to stay in the closed spaces with great surfaces and avoid exploring the empty spaces.
In the granite burying experiment, mice who have high stress are known to repeatedly and forcefully destroy marbles in their bedding.  ,
” It is well known that in mice, stimulants induce reduced marble burying and promote exploration of the empty hands of the plus maze”, said , Christina Kim, the study’s related author and an assistant professor of neurology, key part of the , Center for Neuroscience , and IPN online.
” 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 ). Six hours after receiving the dose, the mice still displayed reduced marble burial and increased open arm time in the elevated plus maze. However, the head twitches associated with hallucinations had disappeared.  ,
We speculated that if we could identify which DOI neurons were responsible for reducing anxiety, we might be able to reactivate them in the future to elicit those anti-anxiety-like effects.  ,
The team used a molecular tagging tool called scFLARE2 to highlight the neurons that DOI in the medial prefrontal cortex, a brain region known to be involved in reducing anxious behavior in mice, activate to identify the specific neural circuits associated with anti-anxiety effects.  ,
The team was able to identify a psychedelic responsive network that goes beyond neurons that express 5-HT2AR, the primary receptor pathway that psychedelics use to 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.
We could still cause a decrease in anxiety-like behaviors when we tagging and reactivating these specific prefrontal cortex cells, Kim said. These changes were measured by decreased marble burying and increased open arm exploration in the elevated plus maze.
Simply put,” We could do this by reactivating the DOI-activated cells the following day.”
The DOI-activated network’s specific neuronal types were genetically profiled by the team using single nucleus RNA sequencing. 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 going on is that we are directly activating the 5-HT2AR-producing cells, which then lead to the activation of additional downstream cells that can change behavior.
She continued,” It is crucial to realize that the cells we are tagging and reactivating go beyond the ones that only express the drug receptor.”
The study emphasizes how one-way communication between multiple brain touchpoints spreads throughout the network.  ,
” While DOI is a potent psychedelic, it is not being explored as a potential therapeutic drug in the clinic. The purpose of the research is to examine the fundamental circuits of this crucial class of drugs, Kim said.
The IPN’s main objective is to find out how psychedelics affect the brain.  ,
Understanding the neural pathways that psychedelics use to produce their effects is the kind of fundamental science required to ultimately create 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.
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 Postdoctoral Training Award from the Canadian Institutes of Health Research, the National Institutes of Health, the Boone Family Foundation, and the Camille Dreyfus Teacher-Scholar Award were all funded by the Burroughs Wellcome Fund.  ,
About this research in psychopharmacology
Author: Andrew Fell
Source: UC Davis
Contact: Andrew Fell – UC Davis
Image: The image is credited to Neuroscience News
Original Research: Closed access.
” Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states” by David E. Olson et al. Science
Abstract
Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states
As alternative therapies for neuropsychiatric disorders, psychedelics may be useful. The neural mechanisms that underlie adaptive behavioral effects are still a mystery.
To find out what specific neurons were involved in driving behavior, we isolated them from a psychedelic. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex ( mPFC) of mice.
Multiple cell types, including those that only had 5-hydroxytryptamine 2A receptors, were the subjects of single-nucleus RNA sequencing that revealed the psychedelic’s ability to network-level activate multiple types of cells.
We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We discovered that these cells ‘ reactivation prevented the psychedelic’s anxiolytic effects from being induced by its hallucinogenic effects.
These findings reveal essential insight into the cell-type–specific mechanisms underlying psychedelic-induced behavioral states.
