Summary: Researchers have identified a novel neurotransmitter system in the brain. The system signals transmission of innate olfactory information to areas of the brain associated with emotional processing via the TAAR5 receptor. The findings could help in the development of new treatments for depression and schizophrenia.
Source: St. Petersburg State University
Neurotransmitters are chemicals that transmit signals between neurons or from neurons to other cells. They interact with specific receptors found in the brain of humans and animals, controlling a variety of biological processes, e.g. fear, anger, pleasure, memory, energy, appetite and sleep. Today, scientists know various types of neurotransmitter systems: dopamine, norepinephrine, serotonin, histamine, glutamate, and many others. A large number of clinically used drugs for many brain disorders is based on the action on these systems.
The St Petersburg University researchers, together with colleagues from the Istituto Italiano di Tecnologia (Genova, Italy) and the Pavlov First St Petersburg State Medical University (St. Petersburg, Russia) conducted experiments on mutant mice. They were able to show that there is a novel neurotransmitter system in the brain – in it, signal transmission of innate olfactory information into the “emotional” brain areas occurs via the trace amine-associated receptor 5 TAAR5.
‘Trace amines are cousins of well-known neurotransmitters dopamine and serotonin,’ explains Raul Gainetdinov. ‘It is known that humans have six subtypes of trace amine-associated receptors that sense trace amines. The TAAR1 receptor is the best investigated, and it is considered so promising that in May 2019, the FDA (Food and Drug Administration, the agency of the US Department of Health and Human Services, which approves the launch of new drugs on the market) designated the experimental drug based on action on TAAR1 of Sunovion Pharmaceuticals the status of “breakthrough treatment” for schizophrenia. Since the FDA accepted the second stage of the clinical trial of their medication for schizophrenia as the third stage, the drug should enter the market within a few years. This should be the first antipsychotic drug in the world that is not a dopamine receptor blocker. It is worth noting that researchers of the St. Petersburg State University are also developing new drugs based on the action on TAAR1.’
Researchers drew attention to another trace amine-associated receptor, TAAR5. It was previously believed that all other receptors for trace amines, with the exception of TAAR1, are exclusively olfactory and participate only in the perception of socially-relevant innate odours (for example, the smell of rotten tissue, predators or pheromones). Therefore, it is believed that they are not useful in the search for novel cures for brain diseases. However, the St. Petersburg State University scientists were convinced of the contrary: to prove the important role of TAAR5 in the neuronal functions and psycho-emotional state, they conducted a series of experiments with knockout laboratory mice – the gene encoding the TAAR5 protein was “knocked out” or “turned off” in these animals. Instead, a marker was inserted into the genome, which allowed the researchers to see in which areas of the brain this protein is present.
‘It turned out that TAAR5 is found not only in the nose and olfactory bulb, but also in the “emotional” brain areas associated with the olfactory system: the amygdala, hippocampus, thalamus and other structures,’ said Professor Gainetdinov. In addition, we observed that the lack of TAAR5 results in the alteration of the concentration of serotonin in the brain, and this is the major indicator of changes in emotional behaviour. Finally, knockout mice without TAAR5 behave as if they are under the treatment with antidepressants or anti-anxiety drugs: they are not afraid of bright light and are not amenable to stress.
Preliminary data also suggest that all other trace amine-associated receptors are not only mediators of the innate olfactory function, but are also variously involved in the regulation of the psycho-emotional state. According to Raul Gainetdinov, this discovery can result in the development of fundamentally new drugs that can deal with schizophrenia, depression, anxiety disorders, various addictions, possibly even Parkinson’s disease and Alzheimer’s disease. The data obtained may have impact to various fields of neuroscience, psychiatry, psychology, and even aromatherapy.
‘Now we have to search for effective antagonists – substances that will block TAAR5 receptors in the brain, thereby exerting an antidepressant and anti-anxiety effect,’ said Raul Gainetdinov. ‘Our laboratory at the St Petersburg University has essentially everything for these studies: we have developed a test system for searching for drugs that activate or block TAAR5 and other receptors; and we also have a unique collection of knockout animals for all receptors for trace amines. We hope to find the support of industrial partners with whom we will be able to develop innovative drugs that no one has created yet. So far, we have investigated only one receptor, TAAR5, which has been previously considered to be an exclusively olfactory receptor. We are performing now studies of four other trace amine-associated receptors, which can open new unexpected directions in the pharmacology of various brain diseases.’
Trace Amine-Associated Receptor 5 Provides Olfactory Input Into Limbic Brain Areas and Modulates Emotional Behaviors and Serotonin Transmission
Trace amine-associated receptors (TAARs) are a class of G-protein-coupled receptors found in mammals. While TAAR1 is expressed in several brain regions, all the other TAARs have been described mainly in the olfactory epithelium and the glomerular layer of the olfactory bulb and are believed to serve as a new class of olfactory receptors sensing innate odors. However, there is evidence that TAAR5 could play a role also in the central nervous system. In this study, we characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO) expressing beta-galactosidase mapping TAAR5 expression. We found that TAAR5 is expressed not only in the glomerular layer in the olfactory bulb but also in deeper layers projecting to the limbic brain olfactory circuitry with prominent expression in numerous limbic brain regions, such as the anterior olfactory nucleus, the olfactory tubercle, the orbitofrontal cortex (OFC), the amygdala, the hippocampus, the piriform cortex, the entorhinal cortex, the nucleus accumbens, and the thalamic and hypothalamic nuclei. TAAR5-KO mice did not show gross developmental abnormalities but demonstrated less anxiety- and depressive-like behavior in several behavioral tests. TAAR5-KO mice also showed significant decreases in the tissue levels of serotonin and its metabolite in several brain areas and were more sensitive to the hypothermic action of serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propilamino)tetralin (8-OH-DPAT). These observations indicate that TAAR5 is not just innate odor-sensing olfactory receptor but also serves to provide olfactory input into limbic brain areas to regulate emotional behaviors likely via modulation of the serotonin system. Thus, anxiolytic and/or antidepressant action of future TAAR5 antagonists could be predicted. In general, “olfactory” TAAR-mediated brain circuitry may represent a previously unappreciated neurotransmitter system involved in the transmission of innate odors into emotional behavioral responses.