The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice

Цыбко, А. С.; Ilchibaeva, Tatiana V.; Filimonova, Elena; Eremin, D.; Попова, Н. К.; Науменко, В. С.

doi:10.1007/s11064-020-03153-5

Cited by 21 publications

(14 citation statements)

References 68 publications

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“…Moreover, the TrkB receptor can be involved in 5-HT 2A -mediated neurito- and spinogenesis in cortical neuronal cultures [ 55 ]. We recently found that the chronic treatment of mice with the selective 5-HT 2A receptor agonists TCB-2 and 25CN-NBOH reduced the levels of total and membrane-associated TrkB protein in the mouse brain [ 56 ], indicating TrkB downregulation. Among several possible explanations for the functional interplay between 5-HT 2A and TrkB, heterodimerization is the most intriguing.…”

Section: Discussionmentioning

confidence: 99%

Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes

Ilchibaeva

Цыбко

Zeug

et al. 2022

Cells

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Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A–TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A–TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.

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Section: Discussionmentioning

confidence: 99%

Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes

Ilchibaeva

Цыбко

Zeug

et al. 2022

Cells

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“…All studies mentioned demonstrating an increase in RRBs following 5-HT2A activation, employed acute administration. One study found no significant impact of chronic 5-HT2A activation on marble burying behavior (Tsybko et al, 2020). Administration of three separate 5-HT2A agonists 25CN-NBOH, TCB2, and DOI over 14 days in C57Bl/6 male mice, did not produce significant changes in marble burying behavior.…”

Section: -Ht2amentioning

confidence: 99%

Impact of specific serotonin receptor modulation on restricted repetitive behaviors

Alvarez

Cavazos

Morales

et al. 2022

Front. Behav. Neurosci.

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Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs.

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“…To realize the true therapeutic potential of psychedelics and other psychoplastogens, we must determine the optimal treatment regimen for several reasons. First, many 5‐HT 2A receptor agonists induce tachyphylaxis, and chronic treatment with psychedelics can result in desensitization of 5‐HT 2A receptors and suppression of BDNF/TrkB signaling (Tsybko et al, 2020). It is important to note that a single high dose of DMT leads to increased spinogenesis in the cortex of rats (Cameron et al, 2018); however, the chronic, intermittent dosing of DMT actually causes spine retraction in the cortex of female rats (Cameron et al, 2019).…”

Section: Key Unanswered Questionsmentioning

confidence: 99%

Psychedelic‐inspired approaches for treating neurodegenerative disorders

Saeger

Olson

2021

Journal of Neurochemistry

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The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice

Cited by 21 publications

References 68 publications

Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes

Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes

Impact of specific serotonin receptor modulation on restricted repetitive behaviors

Psychedelic‐inspired approaches for treating neurodegenerative disorders

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