TY - JOUR

T1 - Unraveling the Serotonergic Mechanism of Stress-Related Anxiety: Focus on Co-Treatment with Resveratrol and Selective Serotonin Reuptake Inhibitors

AU - Tseilikman, Vadim E

AU - Tseilikman, Olga B

AU - Karpenko, Marina N

AU - Traktirov, Dmitrii S

AU - Obukhova, Daria A

AU - Shatilov, Vladislav A

AU - Zhukov, Maxim S

AU - Manuilov, Gennady V

AU - Yegorov, Oleg N

AU - Aristov, Maxim R

AU - Lipatov, Ilya A

AU - Buksha, Irina A

AU - Epitashvili, Alexandr E

AU - Pashkov, Anton A

AU - Novak, Jurica

N1 - This work was supported by the Russian Scientific Foundation, Regional grant, Chelyabinsk Region (№23-15-20040).

PY - 2024/11

Y1 - 2024/11

N2 - Citation: Tseilikman, V.E.; Tseilikman, O.B.; Karpenko, M.N.; Traktirov, D.S.; Obukhova, D.A.; Shatilov, V.A.; Zhukov, M.S.; Manuilov, G.V.; Yegorov, O.N.; Aristov, M.R.; et al. Unraveling the Serotonergic Mechanism of Stress-Related Anxiety: Focus on Co-Treatment with Resveratrol and Selective Serotonin Reuptake Inhibitors. Biomedicines 2024, 12, 2455. https://doi. Abstract: Background/Objectives: In post-traumatic stress disorder (PTSD), anxiety-like symptoms are often associated with elevated noradrenaline levels and decreased serotonin. Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat anxiety, but elevated serotonin has been observed in some anxiety disorders. This study investigates stress-induced anxiety as an immediate effect of chronic stress exposure using the predator stress paradigm. Methods: We examined serotonin levels, serotonin transporter (SERT), and 5-HT 3A receptor gene expression in response to stress. The effects of SSRIs (paroxetine, sertraline) and resveratrol on these parameters were also analyzed, alongside co-treatment with resveratrol and sertraline. Results: Chronic stress exposure led to a significant increase in serotonin levels and upregulation of SERT and 5-HT3A receptor expression. SSRIs failed to prevent anxiety or reduce serotonin levels, partly due to suppressed SERT expression. Resveratrol downregulated SERT and 5-HT3A expression less than SSRIs but effectively reduced anxiety and restored serotonin, likely by upregulating MAO-A expression. Co-treatment with resveratrol and sertraline produced the strongest anxiolytic effect. Conclusions: Elevated serotonin and increased expression of SERT and 5-HT 3A receptor genes are key factors in stress-related anxiety. Resveratrol and SSRIs target these mechanisms, suggesting potential therapeutic strategies for anxiety disorders. Future research will focus on further elucidating the serotonergic mechanisms involved and identifying new anxiolytic drug targets.

AB - Citation: Tseilikman, V.E.; Tseilikman, O.B.; Karpenko, M.N.; Traktirov, D.S.; Obukhova, D.A.; Shatilov, V.A.; Zhukov, M.S.; Manuilov, G.V.; Yegorov, O.N.; Aristov, M.R.; et al. Unraveling the Serotonergic Mechanism of Stress-Related Anxiety: Focus on Co-Treatment with Resveratrol and Selective Serotonin Reuptake Inhibitors. Biomedicines 2024, 12, 2455. https://doi. Abstract: Background/Objectives: In post-traumatic stress disorder (PTSD), anxiety-like symptoms are often associated with elevated noradrenaline levels and decreased serotonin. Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat anxiety, but elevated serotonin has been observed in some anxiety disorders. This study investigates stress-induced anxiety as an immediate effect of chronic stress exposure using the predator stress paradigm. Methods: We examined serotonin levels, serotonin transporter (SERT), and 5-HT 3A receptor gene expression in response to stress. The effects of SSRIs (paroxetine, sertraline) and resveratrol on these parameters were also analyzed, alongside co-treatment with resveratrol and sertraline. Results: Chronic stress exposure led to a significant increase in serotonin levels and upregulation of SERT and 5-HT3A receptor expression. SSRIs failed to prevent anxiety or reduce serotonin levels, partly due to suppressed SERT expression. Resveratrol downregulated SERT and 5-HT3A expression less than SSRIs but effectively reduced anxiety and restored serotonin, likely by upregulating MAO-A expression. Co-treatment with resveratrol and sertraline produced the strongest anxiolytic effect. Conclusions: Elevated serotonin and increased expression of SERT and 5-HT 3A receptor genes are key factors in stress-related anxiety. Resveratrol and SSRIs target these mechanisms, suggesting potential therapeutic strategies for anxiety disorders. Future research will focus on further elucidating the serotonergic mechanisms involved and identifying new anxiolytic drug targets.

KW - chronic stress

KW - dopamine

KW - hippocampus

KW - mRNA

KW - noradrenaline

KW - receptors

KW - resveratrol

KW - serotonin

UR - https://doi.org/10.3390/biomedicines12112455

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85210429724&origin=inward&txGid=5ac33b400774cfae0a07e257f6d4d3a0

UR - https://www.mendeley.com/catalogue/67b83237-0d7e-377c-9f08-259cec718e52/

U2 - 10.3390/biomedicines12112455

DO - 10.3390/biomedicines12112455

M3 - Article

C2 - 39595020

VL - 12

JO - Biomedicines

JF - Biomedicines

SN - 2227-9059

IS - 11

M1 - 2455

ER -