Summary: New analysis has identified the particular head region and nerve type that help patients take the psychedelic medicine DOI without triggering hallucinations. The research revealed that DOI targets serotonin2A synapses on parvalbumin-positive cells in the lateral brain, decreasing anxiety actions in dog models.
Amazingly, this head circuit is distinct from those causing hallucinations, offering ability for stress treatments without delusional effects. The results pave the way for psychedelic-inspired medicines that could properly maintain anxiety disorders.
Important Information:
- The trippy DOI reduces stress by targeting serotonin2A receptor in the lateral hippocampus.
- The brain’s components responsible for delusions are distinct from those responsible for anxiety.
- Activating certain cells in this region replicates DOI’s anxiety-reducing results.
Origin: Tata Institute of Fundamental Research
Psychoedelics have been around for thousands of years in indigenous cultures, and there is empirical proof of their changing effects on mood and belief.
There has just been a resurgent interest in psychedelics because they have potent medical effects on psychiatric disorders like anxiety and depression. However, it has remained a secret as to how psychedelics really bring about changes in mood-related actions.
A team of researchers led by Prof. Vidita Vaidya of TIFR Mumbai mapped the specific region of the brain and the specific group of cells that account for the increases in stress brought on by psychedelic DOI after working with research teams from Cornell, Columbia, and Yale University.
On approach-avoidance cognitive tasks like the raised in jungle and empty field test, the psychedelic DOI, when administered to rats or mice regionally, reduces anxiety behavior.
Local infusions of the drug into targeted brain regions revealed a crucial role of the ventral hippocampus in mediating this effect of the psychedelic DOI. To precisely pinpoint the region of the brain that responds to DOI and drives this decrease in anxiety behavior, local infusions of the drug were conducted.
Further, the study uncovered that the psychedelic DOI targets the serotonin2A , receptor in the ventral hippocampus to exert its effects on anxiety. The team also rejected contributions from other brain regions, including the prefrontal cortex and the amygdala at the same time.
What was remarkable was that the ventral hippocampus, which is essential for the reduction in anxiety caused by DOI, did not cause hallucinations, demonstrating that psychedelics target various parts of the brain to cause a wide range of behavioral changes.
Electrophysiological studies revealed that the psychedelic DOI increased the firing of parvalbumin-positive, fast-spiking, interneurons in the ventral hippocampus, which express the serotonin2A , receptor. This identified the potential cellular trigger that the psychedelic DOI might use to lessen anxiety.
In order to behaviorally test this, chemogenetic strategies were employed to activate this specific subclass of neurons within the ventral hippocampus in the absence of the psychedelic DOI, which was sufficient to reduce anxiety behavior in animal models.
Further, selective restoration of the serotonin2A , receptor on parvalbumin neurons was sufficient to restore the decline in anxiety seen on treatment with the psychedelic DOI in the ventral hippocampus using a genetic knockout mouse model that lacked any serotonin2A , receptor in the brain and body.  ,
Together, using genetic, pharmacological, electrophysiological and behavioral studies, the team identified parvalbumin-positive, fast-spiking, interneurons in the ventral hippocampus as the cellular trigger through which the psychedelic DOI can reduce anxiety.
This provides the first clear indication of a precise mapping of the brain region and neuronal population whose specific psychedelics are known to influence anxiety behavior.
It also provides the intriguing possibility of using psychedelic-inspired drugs that have therapeutic potential for the treatment of anxiety disorders without having potent hallucinogenic effects because it also demonstrated that this brain circuit does not cause altered perception and hallucinations.  ,
About this research in the areas of anxiety and psychopharmacology
Author: Nisha Yadav
Source: Tata Institute of Fundamental Research
Contact: Nisha Yadav – Tata Institute of Fundamental Research
Image: The image is credited to Neuroscience News
Original Research: Open access.
Vidita A. Vaidya and colleagues ‘” The serotonergic psychedelic DOI’s ventral hippocampal parvalbumin interneurons control the acute anxiolytic action of the serotonergic psychedelic interneurons..” Neuron
Abstract
The serotonergic psychedelic DOI’s ventral hippocampal parvalbumin interneurons control the acute anxiolytic action of the serotonergic psychedelic interneurons.
Recently, serotonergic psychedelics have rekindled interest in their therapeutic potential. In the anxiolytic effect evoked by the serotonergic psychedelic 2, 5-dimethoxy-4-iodoamphetamine ( DOI), we reveal the crucial role of ventral hippocampus (vHpc ) GABAergic interneurons.
Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A , receptors in the CA1/subiculum ( CA1/sub ) region of the vHpc are required for the anxiolytic action of DOI.  , In , vivo , electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin ( PV ) -positive interneurons, most of which express the 5-HT2A , receptors.
Restoration of 5-HT2A , receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region.
Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT2A , receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior.
