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-HT$3A$ receptor expression. SSRIs failed to prevent anxiety or reduce serotonin levels, partly due to suppressed SERT expression. Resveratrol downregulated SERT and 5-HT$3A$ 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.

Background/Objectives: The therapeutic potential of selective trace amine-associated receptor 1 (TAAR1) agonists has been established in multiple animal models of depression and anxiety. PTSD is a debilitating psychiatric disorder frequently characterized by anxiety and often comorbid with major depressive disorder. Complex PTSD represents an even more severe clinical presentation, emerging from prolonged or repeated exposure to traumatic events. Recent studies indicate that TAAR1 agonists can attenuate anxiety-like behaviors in experimental models of PTSD; however, the molecular mechanisms underlying this effect remain poorly understood. In this study, we evaluated whether TAAR1 agonism modulates PTSD-related neurochemical and molecular changes within the hippocampus and striatum. Methods: Post-traumatic stress was modeled using predator stress, a validated experimental paradigm relevant to complex PTSD. Treatment consisted of intraperitoneal administration of the TAAR1 agonist LK00764. Monoamine neurotransmitters and their metabolites were quantified, and the expression of genes implicated in noradrenergic, dopaminergic, and serotonergic signaling pathways was assessed. In addition, gene network reconstruction was performed using artificial intelligence to identify TAAR1-dependent regulatory interactions. Results: Treatment with a TAAR1 agonist fully prevented behavioral abnormalities in the experimental model of complex PTSD. Neurochemical analyses revealed decreased 5-HT levels in the hippocampus and reduced dopamine and metabolite concentrations in the striatum following TAAR1 agonism. Moreover, TAAR1 activation was associated with increased expression of the neurotrophic factor BDNF in the striatum. Gene network reconstruction identified a distinct molecular hub within the PTSD network, comprising TAAR1-coexpressed genes, their encoded proteins, and interconnected signaling pathways, suggesting a tightly regulated feedback loop. Conclusions: These findings provide novel evidence that TAAR1 agonists exert protective effects against complex PTSD-related behavioral and neurochemical abnormalities. The reconstructed TAAR1-centered gene network offers mechanistic insight into receptor-dependent regulation of monoaminergic signaling and neuroplasticity, supporting further exploration of TAAR1 agonists as promising therapeutic candidates for PTSD.

Chronic exposure to manganese compounds leads to accumulation of the manganese in the basal ganglia and hippocampus. High levels of manganese in these structures lead to oxidative stress, neuroinflammation, imbalance of brain neurotransmitters, and hyperactivation of calpains mediating neurotoxicity and causing motor and cognitive impairment. The purpose of this work was to study the effect of excess manganese chloride intake on rats' spatial memory and on dopamine-β-hydroxylase (DβH) activity under conditions of calpain activity suppression. Rats were divided into 3 groups of 10 animals each. Group 1 received MnCl₂ (30 days, 5 mg/kg/day, intranasally), group 2 received MnCl₂ (30 days, 5 mg/kg/day, intranasally) and calpain inhibitor Cast (184-210) (30 days, 5 µg/kg/day, intranasally), and group 3 received sterile saline (30 days in a volume of 20 μl, intranasally). The spatial working memory was assessed using Morris water maze test. DβH activity was determined by HPLC. We have shown that in response to excessive intake of MnCl₂, there was a development of cognitive impairments in rats, which was accompanied by a decrease in DβH activity in the hippocampus. The severity of cognitive impairment was reduced by inhibiting the activity of m-calpain. The protective effect of calpain inhibitors was achieved not through an effect on DβH activity. Thus, the development of therapeutic regimens for the treatment of manganism using dopaminomimetics and/or by inhibiting calpains, must be performed taking into account the manganese-induced decrease of DβH activity and the inability to influence this process with calpain inhibitors.

BACKGROUND: Glucocorticoids play an important role in the development of the stress response in the organism. Synthetic glucocorticoids such as dexamethasone are widely used in medicine due to their anti-inflammatory effects. However, there is evidence that glucocorticoid-based drugs used in sufficiently high doses can induce pro-inflammatory effects by affecting predominantly the hippocampus in the central nervous system as the most plastic brain structure. It is important to note that the dose, route and timing of administration can affect the effects of glucocorticoids, and it is therefore an important biomedical task to choose the optimal parameters of glucocorticoid administration in order to achieve the most effective treatment results. AIM: The aim of our study was to investigate the effect of peripheral administration of a synthetic glucocorticoid, dexamethasone, at a dose of 8 mg/kg on the development of neuroinflammation in the rat hippocampus at different periods after administration. MATERIALS AND METHODS: Thirty-two sexually mature male Wistar rats distributed into 8 groups of 4 animals each were used in the experiment. The animals were injected with dexamethasone at a dose of 8 mg/kg and decapitated for different periods (1, 3, 9, 12, 18, 24, 48 hours — time of decapitation after administration), group К — control group with saline injection). Further, the cytokine profile expression was analyzed by real-time reverse transcription polymerase chain reaction method. RESULTS: In this study, we found an increase in the expression of proinflammatory cytokines AIF1 (IBA-1) and IL-1β after 12 and TNF-α after 24 hours after dexamethasone administration at a dose of 8 mg/kg, which may indicate a neuroinflammatory effect of dexamethasone at this dose. It should be noted that the level of NF-êB gene, a marker of inflammation, remained unchanged, possibly due to the activation of compensatory mechanisms to control inflammation or stress. CONCLUSIONS: The increase in mRNA of inflammatory markers IL-1β, TNF-α and AIF1, in the hippocampus after 12 hours after single dexamethasone administration to rats at a dose of 8 mg/kg may indicate a switch of the effect of this drug from antiinflammatory to proinflammatory, which should be taken into account when dexamethasone is used such a treatment during several diseases.