Offensive Behavior, Striatal Glutamate Metabolites, and Limbic–Hypothalamic–Pituitary–Adrenal Responses to Stress in Chronic Anxiety

Ullmann, Enrico; Chrousos, George P.; Perry, Seth W.; Wong, Ma Li; Licinio, Júlio; Bornstein, Stefan R.; Tseilikman, Olga; Komelkova, Maria; Lapshin, Maxim; Vasilyeva, Maryia; Zavjalov, Evgenii L.; Shevelev, Oleg B.; Khotskin, Nikita V.; Koncevaya, Galina V.; Khotskina, Anna S.; Мошкин, М. П.; Черкасова, О. П.; Sarapultsev, Alexey; Ibragimov, Roman; Kritsky, Igor; Fegert, Jörg M.; Tseĭlikman, Vadim; Yehuda, Rachel

doi:10.3390/ijms21207440

Cited by 12 publications

(26 citation statements)

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“…The mechanism of the moderating role of glutamate within the limbic stress system circuits is largely unknown, however, lower glutamate levels in the amygdala of more active subjects seems to be associated with less anxiety and decreased plasma cortisol (CORT) levels ( 3 ). On the other hand, lower glutamate levels in the striatum were associated with lower adrenal 11-dehydrocorticosterone and higher plasma CORT ( 5 ). These inverse reaction patterns of the limbic Glu-Cort circuits could be explained by the paradigms of caco- and hyper-stasis ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that obese humans, labeled as low cortisol reactors, consume less food, and that more active and “offensive” rats have low levels of anxiety and increased glutamate+glutamine levels in the striatum and inversely related glutamate levels in the amygdala ( 3 – 5 ). These pathophysiological limbic circuit changes are present not only in patients with obesity and/or less physical activity, but also in patients with PTSD ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

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Lamotrigine Reduces Stress Symptoms of Chronic Anxiety in the Times of the Covid-19 Natural Catastrophe-A Case Report

et al. 2021

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The SARS-CoV-2 pandemic has been a worldwide chronic, stress-inducing natural catastrophe associated with increased emotional challenging. Patients with Post-traumatic stress disorder (PTSD), self-injury behavior, and obesity are predisposed to aggravation of their symptoms at this time, requiring new therapeutic approaches to balance their disrupted neuro-hormonal stress axis. Here we present our observations of an off-label treatment with lamotrigine in an adolescent girl with PTSD, self-injury behavior, and obesity. Lamotrigine was an efficacious pharmaceutical intervention that helped the patient deal with chronic stress and associated anxiety. The results are discussed based on our previous basic research outcomes in animals and humans that focused on the glutamate-cortisol circuits within the limbic brain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lamotrigine Reduces Stress Symptoms of Chronic Anxiety in the Times of the Covid-19 Natural Catastrophe-A Case Report

et al. 2021

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“…Furthermore, we previously reported that chronic predator scent stress (PSS)-induced PTSD was accompanied by adrenal damage, especially in the GC-producing zona fasciculata, as well as plasma corticosterone (CORT) reduction [8]. Moreover, we found inverse CORT levels in high-vs. low-anxiety allostatic flight/fight/active (AFR) or allostatic freezing/passive (APR) responders to chronic stress [9]. However, no histomorphological data related to CORT reduction in chronically stressed subjects are available.…”

Section: Introductionmentioning

confidence: 99%

A Rat Model of Post-Traumatic Stress Syndrome Causes Phenotype-Associated Morphological Changes and Hypofunction of the Adrenal Gland

Tseĭlikman

Komelkova

Kondashevskaya

et al. 2021

IJMS

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Background: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. Methods: Rats were exposed to PSS for ten days. Thirty days later, the rats’ anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. Results: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. Conclusion: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.

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“…Converging evidence suggests that the striatum as one of the important neural substrates is disturbed in the reward circuitry of depression and anxiety by stress ( Admon et al, 2015 ; Ullmann et al, 2020 ; Martin-Soelch et al, 2021 ). In the present work, the striatal site-specific proteomic signatures of the three stressed and Ctrl groups were comparatively determined through the use of an iTRAQ-based quantitation strategy.…”

Section: Discussionmentioning

confidence: 99%

“…Striatal dopamine D2/3 receptor-mediated neurotransmission is also reported to be involved in the pathophysiology of anxiety and depression ( Schneier et al, 2008 ; Nikolaus et al, 2010 ; Leggio et al, 2015 ; Admon et al, 2017 ; Peciña et al, 2017 ). The striatum may be a structure in which stress and reward processing interact ( Admon et al, 2015 ; Ullmann et al, 2020 ). Specifically, stress, on the other hand, reduces the activation of the striatum in response to reward and elicits robust dopamine release in the striatum on the other ( Martin-Soelch et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Proteomic Insights Into Susceptibility and Resistance to Chronic-Stress-Induced Depression or Anxiety in the Rat Striatum

Cai

Yang

Chen

et al. 2021

Front. Mol. Biosci.

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Chronic stress is a key factor for the onset of anxiety and depression disorders. However, the stress-induced common and unique molecular basis of the two psychiatric disorders is not fully known and still needs to be explored. Previously, we employed a chronic mild stress (CMS) procedure to induce a rat model including depression-susceptible (Dep-Sus), anxiety-susceptible (Anx-Sus), and insusceptible (Insus) cohorts. In this work, we continuously analyze the striatal proteomes of the three stressed cohorts by the use of comparative proteomics and bioinformatics approaches. Through isobaric tags for relative and absolute quantitation (iTRAQ)-based analysis, 386 abnormally expressed proteins in total were identified. These deregulated proteins are involved in various biological functions and significant pathways that are potentially connected with resistance and susceptibility to CMS-caused anxious- or depressive-like behaviors and, hence, could act as suggestive protein targets. A further parallel reaction monitoring-based independent investigation shows that alterations in Pak5, Dgkg, Scn4b, Rb1cc1, and Acin1; Ggps1, Fntb, Nudt19, Ufd1, and Ndufab1; and Dnajb12, Hbb2, Ap2s1, Ip6k1, and Stk4 were specifically connected with Dep-Sus, Anx-Sus, or Insus groups, respectively, potentially indicating that identical CMS treatment results in the different changes in the striatal protein regulations. Overall, our current proteomics study of the striatum provides an important molecular foundation and comprehensive insights into common and specific deregulations correlated with pathophysiological mechanisms that underlie resistance and susceptibility to chronic stress–induced anxiety or depression.

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Offensive Behavior, Striatal Glutamate Metabolites, and Limbic–Hypothalamic–Pituitary–Adrenal Responses to Stress in Chronic Anxiety

Cited by 12 publications

References 62 publications

Lamotrigine Reduces Stress Symptoms of Chronic Anxiety in the Times of the Covid-19 Natural Catastrophe-A Case Report

Lamotrigine Reduces Stress Symptoms of Chronic Anxiety in the Times of the Covid-19 Natural Catastrophe-A Case Report

A Rat Model of Post-Traumatic Stress Syndrome Causes Phenotype-Associated Morphological Changes and Hypofunction of the Adrenal Gland

Proteomic Insights Into Susceptibility and Resistance to Chronic-Stress-Induced Depression or Anxiety in the Rat Striatum

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