Researchers at the University of Arizona College of Medicine – Phoenix identified the effects of an environmental stressor, sleep deprivation, that could alter the balance controlled by antipsychotics and affect those with schizophrenia.
The serotonin 2A (5-HT2A) receptor is widespread in the brain and plays a crucial role in perception, cognition and psychosis. It is also responsible for the psychedelic effects of drugs like psilocybin (hallucinogenic mushrooms) and LSD. Abnormal 5-HT2A receptor function has been linked to psychiatric disorders, including schizophrenia. The leading class of antipsychotics for the treatment of schizophrenia targets 5-HT2A receptors to reduce symptoms of hallucinations and impaired cognition.
A study led by Amelia Gallitano, MD, PhD, a professor in the Department of Basic Medical Sciences and Psychiatry at the University of Arizona College of Medicine – Phoenix found that an environmental stressor, sleep deprivation, can significantly increase serotonin 2A neurotransmitter levels in 6 to 8 hours in an animal model. In people with schizophrenia, these results suggest that environmental stressors can alter the balance of brain receptors that are controlled by antipsychotics.
“Our study shows that environmental stimuli can change the concentration of receptors that play an important role in the brain within hours,” says Gallitano, whose laboratory focuses on studying the interaction between environmental stress and genetic predisposition in the development of psychiatric diseases . “Now we think we know the mechanism by which this happens; it is through the EGR3 gene.
The role of 5-HT2A Receptors in controlling one’s ability to understand and process information have been extensively studied. However, the signaling process that regulates this gene expression is still poorly understood – until now.
Receptor proteins on the surface of brain cells control the brain’s internal communication network. These receptors are created when a gene (region of DNA) is activated and produces the instructions (messenger RNA) that the cell uses to make the protein, in this case the 5-HT2A receptor. How many of the receptors are made and present on the cell surface determines how the brain cell reacts to the neurotransmitter serotonin and also to drugs that bind to the receptor, such as antipsychotics, LSD and psilocybin.
The 5-HT2A receptor receives its coded instruction from the HTR2A gene. The study found that proteins produced by EGR3, a gene responsible for an early growth response, are also required for expression of the 5-HT2A receptor.
The function of EGR3 is to bind to DNA and turn other genes on and off. The results showed that stimuli caused by sleep deprivation caused EGR3 to bind to the 5-HT2A receptor gene and turn on its production of mRNA instructions to make more protein. This resulted in more 5-HT2A receptors in the brain within a few hours.
Consequences for schizophrenia
The results of this study improve our understanding of how the environment alters the expression of brain receptors that mediate prefrontal cortex function. Activity in the brain’s prefrontal cortical region is essential for spatial thinking and working memory. Dysfunction in this area can contribute to the cognitive deficits that are characteristic of schizophrenia.
Schizophrenia is a mental illness that is characterized by abnormalities in perception, thinking, and memory. The disease disrupts the processes of perception, sleep and memory, which leads to the fact that patients experience hallucinations and loss of reality.
In the search for treatments for severe psychiatric symptoms, drugs that trigger a physiological response by binding to 5-HT2A receptors are experiencing a resurgence. The fact that 5-HT2A receptors mediate the hallucinogenic effects of drugs like LSD and psilocybin suggests that this receptor influences the hallucinations and cognitive disorders of schizophrenia.
“We want to understand the genes that are expressed as a result of environmental stimuli and how this gene-environment interaction influences behavior changes that can lead to symptoms of mental illness,” said Gallitano.
Relation: Zhao X, Ozols AB, Meyers KT et al. Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3. Mol psychiatry. 2022: 1-12. doi: 10.1038 / s41380-021-01390-w
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