The institute's scientists have developed a method for detecting the neurological effects of psychedelic drugs. Middle: Zebrafish on hallucinogenic mushrooms. The goal: to pave the way for more effective treatments for depression and other mood disorders
Psychedelic drugs are a sought-after commodity in research laboratories around the world. Not because of the mind-altering qualities, but because of the promise inherent in them for the treatment of mental disorders and in particular anxiety disorders and depression. However, the road to effective and safe drugs based on hallucinogenic mushrooms and other psychoactive substances is still not paved - we simply do not know enough about how they work in the body.
In a new study, QRecently published in the scientific journal Molecular Psychiatry, presented a team led by dr Takashi Kawashima From the Weizmann Institute of Science a new approach that allows examining the effect of psychedelic substances both at the behavioral level and at the level of the neural activity of individual cells in the brain. This approach is made possible through a combination of powerful optical microscopy, artificial intelligence, and not least a model animal with a surprising resemblance to humans and fins: zebrafish. In the study, the researchers demonstrated the new approach to psilocybin, a psychedelic substance extracted from hallucinogen mushrooms, and showed that it has a unique effect: it relaxes and stimulates at the same time.
Fish on drugs
Psychedelic drugs have been used by humans for thousands of years - from ancient shamanic rituals to "Burning Man". Although they are outlawed in most countries, in recent years there has been a growing openness to using these substances for research purposes. For example, in the focus of some current studies are psychedelic substances that affect serotonin - a neurotransmitter that regulates mood and is involved in anxiety disorders and depression. Despite the growing openness to psychedelia in science, research into these substances still poses difficult challenges. First, as their name suggests, these are hallucinogenic substances that may even be dangerous - therefore the ability to examine their effect on humans is extremely limited. Secondly, these substances affect neural circuits located in the depths of the brain, so it is difficult to observe the activity that occurs in them with the existing imaging methods. "Fortunately, newborn zebrafish are completely transparent," says Dr. Kawashima, "this feature allows researchers to monitor the effect of different substances on specific brain cells and link it to a certain behavior."
Selective increase of serotonin level
The present study was born out of the initiative of Dr. Dotan Brown, a psychiatrist who joined Dr. Kawashima's laboratory as a visiting scientist, also a physician by training, in the neuroscience department of the Weizmann Institute of Science. Dr. Brown was impressed by the method developed by Dr. Kawashima for imaging brain activity in zebrafish and his research on serotonin activity in the brain, and suggested that he work together on a project that would advance the understanding of how psychedelic substances affect the serotonin system.
"The treatments commonly used today to treat anxiety disorders and depression, drugs such as ciprofloxacin or Prozac from the SSRI family, work through a mechanism that leads to raising serotonin levels in all areas of the brain," explains Dr. Brown, "Psychedelic substances, on the other hand, work on serotonin receptors through a mechanism Another, much faster, and they seem to affect much more targeted brain areas. A better understanding of the mechanism of action of these substances and the mapping of their areas of influence may make it possible to develop more effective drug treatments with fewer side effects."
To this end, the researchers developed an experimental set-up that allows "getting inside the head" of zebrafish that have been exposed to psychedelic substances. After a four-hour immersion in a "psychedelic bath" that included a psilocybin solution, the transparent fry that participated in the experiment were transferred to a shallow pool of clean water. At this point, similar to the "ice pools" trend, the researchers suddenly lowered the water temperature in the pool. "We wanted to see how psychedelic substances affect the fish's stress response," says Dr. Kawashima and adds with a smile: "We discovered that just like with humans, when you're stressed about something, a long bath can help."
Indeed, the researchers found that the psychedelic bath reduced stress-related behaviors in two different and complementary ways: despite the exposure to cold, the fish exposed to the psychedelic substance tended to move around the aquarium and explore their surroundings, including distant and dim corners, more than the fish in the control group that did not receive their dose of the drug. Also, the "drugged" fish moved faster compared to the control swimmers. These two findings indicated a stimulant effect of psilocybin.
But alongside the stimulating effect, a calming and anxiety-reducing effect was also recorded. "Fish that did not swim in the psilocybin solution responded to the sudden drop in temperature with an irregular zig-zag swimming pattern," says Ayelet Rosenberg, a research student in Dr. Kawashima's laboratory. "In contrast, the fish that were treated with the psychedelic drug remained calm. You can say that they 'flowed' with the stress more easily."
The scientists were able to identify the differences in the behavior of the fish by recording each of them swimming in the aquarium before being soaked in the psilocybin bath and after the immersion. They tracked their movement using a high-speed camera that produced 270 images in each 15-minute experiment, and then manually divided the images into ten categories according to the fish's body parts - from eyes and nostrils to six different points along the length of the tail.
This data was used to train an advanced artificial intelligence algorithm so that it could recognize the behavior patterns of the fish. Following the training, the algorithm was able to map subtle changes in the fish's swimming patterns under the influence of the psychedelic substances. In the next step, the researchers created an affinity between the changes in the behavior of the fry and the changes in the activity of specific neural circuits. To this end, they used a fluorescent labeling method developed by Dr. Kawashima in previous studies. This method makes it possible to literally illuminate the activity of neural circuits in the depths of the transparent fish brains and reveal this activity with the help of a powerful optical microscope.
"The microscope revealed patterns of neural activity that were similar to those previously discovered in the brains of mammals exposed to psychedelic substances," says Dr. Kawashima. "This finding indicates that psilocybin affects behaviors through neural mechanisms located in deep areas of the brain that have been preserved during evolution and also characterize mammals, including humans."
Although research of psychedelic substances in fish is limited in many respects; For example, it is not at all clear if the fish is experiencing hallucinations and perhaps even imagines that it is a hedgehog. However, the new research method opens the door to a better understanding of the effects of psychedelic substances and may advance future treatments based on these substances. Says Dr. Kawashima: "Although our research focused on fish, its implications are much broader: it paves the way for discovering the mechanisms of action of psychedelic substances and even for a better understanding of the mechanisms of action of various mood disorders."
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