Chemogenetic inhibition of central amygdala CRF-expressing neurons decreases alcohol intake but not trauma-related behaviors in a rat model of post-traumatic stress and alcohol use disorder

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(9), P. 2611 - 2621

Published: March 21, 2024

Post-traumatic stress disorder (PTSD) and alcohol use (AUD) are often comorbid. Few treatments exist to reduce comorbid PTSD/AUD. Elucidating the mechanisms underlying their comorbidity could reveal new avenues for therapy. Here, we employed a model of PTSD/AUD, in which rats were subjected stressful shock familiar context followed by drinking. We then examined fear overgeneralization irritability these rats. Familiar elevated drinking, increased overgeneralization, alcohol-related aggressive signs, peripheral hormones. transcripts stress- fear-relevant genes central amygdala (CeA), locus that regulates stress-mediated Compared with unstressed rats, stressed exhibited increases CeA Crh Fkbp5 decreases Bdnf Il18. Levels Nr3c1 mRNA, encodes glucocorticoid receptor, males but decreased females. Transcripts Il18 binding protein (Il18bp), Glp-1r, associated calcitonin gene-related peptide signaling (Calca, Ramp1, Crlr-1, Iapp) unaltered. Crh, not Crhr1, mRNA was stress; thus, tested whether inhibiting neurons express corticotropin-releasing factor (CRF) suppress PTSD/AUD-like behaviors. used Crh-Cre had received Cre-dependent vector encoding hM4D(Gi), an inhibitory Designer Receptors Exclusively Activated Drugs. Chemogenetic inhibition CRF reduced intake or irritability-like Our findings suggest modulates PTSD/AUD comorbidity, neural activity is primarily reducing drinking trauma-related behaviors

Language: Английский

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Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD

Psychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Abstract Rationale Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine’s acute treatment effects post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for development of targeted interventions. Objectives systematic review examines pharmacokinetic pharmacodynamic ketamine PTSD, differentiating between immediate effects. Method A comprehensive search across databases (Web Science, Scopus, Global Health, PubMed) grey literature yielded 317 articles, where 29 met inclusion criteria. These included preclinical models clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, neural pathways (PROSPERO ID: CRD42024582874). Results We found accumulating evidence that ketamine, involve changes in GABA, glutamate, glutamine levels, trigger re-regulation BDNF, enhancing plasticity via such as TrkB PSD-95. Other influences also include c-Fos, GSK-3, HDAC, HCN1, modulation hormones like CHR ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained arise from remodulations prolonged expression. mTOR-mediated BDNF alterations GSK-3β, FkBP5, GFAP, ERK phosphorylation, epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC). Conclusion promote long-term stability key brain regions, contributing to benefits. Understanding behind ketamine’s is critical developing safe effective personalised treatments, potentially leading more recovery.

Language: Английский

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Sex-dependent factors of alcohol and neuroimmune mechanisms

Neurobiology of Stress, Journal Year: 2023, Volume and Issue: 26, P. 100562 - 100562

Published: Aug. 3, 2023

Excessive alcohol use disrupts neuroimmune signaling across various cell types, including neurons, microglia, and astrocytes. The present review focuses on recent, albeit limited, evidence of sex differences in biological factors that mediate responses to underlying systems may influence drinking behaviors. Females are more vulnerable than males the neurotoxic negative consequences chronic drinking, reflected by elevations pro-inflammatory cytokines inflammatory mediators. Differences cytokine, microglial, astrocytic, genomic, transcriptomic suggest females reactive neuroinflammatory changes after exposure. growing body supports innate immune modulate synaptic transmission, providing a mechanistic framework examine sex-differences neurocircuitry. Targeting be viable strategy for treating AUD, but research is needed understand sex-specific mechanisms.

Language: Английский

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GABA release from central amygdala neurotensin neurons differentially modulates ethanol consumption in male and female mice

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 49(7), P. 1151 - 1161

Published: Feb. 28, 2024

Language: Английский

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Interleukin 18 and the brain: neuronal functions, neuronal survival and psycho-neuro-immunology during stress

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

Language: Английский

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Circulating Immune and Endocrine Markers in Currently Drinking and Abstinent Individuals With Alcohol Use Disorder and Controls

Addiction Biology, Journal Year: 2025, Volume and Issue: 30(5)

Published: May 1, 2025

ABSTRACT Alcohol use disorder (AUD) is associated with changes in endocrine and immune system function. This study a secondary analysis aimed at investigating circulating biomarkers blood samples from three groups: (1) healthy controls (HC, N = 12), (2) AUD—currently drinking, nontreatment seeking (CD, 9), (3) AUD—abstinent, treatment‐seeking (AB, 10; abstinent for least 6 weeks). We hypothesized that both biomarker concentrations would be different AUD groups compared to controls. Immune included IL‐8, IL‐18, CCL2, TNF‐α, IL‐1RA, IL‐6, IL‐10. Endocrine brain‐derived neurotrophic factor (BDNF), glucagon‐like peptide 1 (GLP‐1), ghrelin, gastric inhibitory (GIP), growth hormone, leptin, insulin. Biomarker were between the while controlling age sex, associations behavioral measures explored. IL‐8 elevated AB CD HC ( F (2,29) 6.33, p 0.006, ƞ 2 0.318). BDNF lower (2,30) 4.34, 0.02, 0.266). GLP‐1 higher (2,25) 4.22, 0.03, 0.287). Exploratory analyses combined showed of past severity, anxiety/depression positively correlated IL‐18 TNF‐α negatively BDNF. These results demonstrate proteins are altered individuals history severe (AB group) In contrast, no group differences observed any seeking, currently drinking people group. Our findings highlight importance accounting comorbidities, status, especially when studying alcohol‐related biomarkers.

Language: Английский

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GABA Release From Central Amygdala Neurotensin Neurons Differentially Modulates Reward and Consummatory Behavior in Male and Female Mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 14, 2023

Abstract The central nucleus of the amygdala is known to play key roles in alcohol use and affect. Neurotensin neurons have been shown regulate drinking male mice. However, little about which neurotransmitters released by these cells drive consumption or whether female Here we show that knockdown GABA release from neurotensin using a Nts- cre-dependent vGAT-shRNA-based AAV strategy reduces male, but not female, This manipulation did impact avoidance behavior, except fasted novelty-suppressed feeding test, vGAT shRNA mice demonstrated increased latency feed on familiar high-value food reward, an effect driven In contrast, showed heightened sensitivity thermal stimulation. These data role for modulating rewarding substances different motivational states.

Language: Английский

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Expression pattern of long non-coding RNAs in treatment-naïve and medicated schizophrenia patients

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 12, 2024

Schizophrenia is a disabling mental disorder that affects 1% of people over their lifetime. The etiology and mechanism schizophrenia are very complex, many genes involved in different signaling pathways the this disease. According to recent studies, one important mechanisms altered regulation immune system inflammation mechanism. In present study, we evaluated peripheral blood expression pattern four lncRNAs three protein-coding treatment- naïve patients, medicated patients compared with sex age-matched controls. medicated-patients, levels IFNG, IL18RAP, AC007278.2 were significantly up-regulated (P < 0.05); level IFNG-AS1-001 was down-regulated healthy controls 0.05). However, IL18R1, AC007278.3 IFNG-AS1-003 not between these groups. treatment-naïve IFNG-AS1-001, AC007278.2, On other hand, Based on Spearman correlation matrix, there significant patients. We also showed high sensitivity specificity IFNG-AS1-003, identification from current study contributes further evidence understanding role pathogenesis schizophrenia. Future research necessary establish validity as markers for condition.

Language: Английский

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Post-traumatic stress disorder: molecular mechanisms of the intergenerational and transgenerational inheritance

Успехи физиологических наук, Journal Year: 2024, Volume and Issue: 55(4), P. 3 - 26

Published: Dec. 8, 2024

Post-traumatic stress disorder is a mental that closely associated with dysfunction of the hypothalamic-pituitary-adrenal axis, and for its development required experience traumatic event causes negative emotions memories persist quite long time. The likelihood post-traumatic influenced both environmental factors, genetic epigenetic characteristics body. In this case modifications act as dynamic biomarkers (“nanotags”) impact environment on genome (epigenome), which can, under certain conditions, disappear or remain not only in an individual directly exposed to psychogenic trauma, but also transmitted over number generations. Review focuses possible mechanisms intergenerational transgenerational inheritance biological effects stress-related disorders.

Language: Английский

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Central Amygdala Neuroimmune Signaling in Alcohol Use Disorder

Addiction Neuroscience, Journal Year: 2024, Volume and Issue: 14, P. 100194 - 100194

Published: Dec. 21, 2024

Alcohol Use Disorder (AUD) is a prevalent and debilitating condition characterized by an inability to control alcohol consumption despite adverse consequences. Current treatments for AUD, including FDA-approved medications such as naltrexone acamprosate, have limited efficacy compliance, underscoring the need novel therapeutic approaches. The central amygdala (CeA) plays crucial role in development maintenance of particularly aspects associated with stress binge behaviors. Recent research indicates neuroimmune signaling CeA emerging key factor this process. Chronic disrupts signaling, leading altered cytokine expression activation glial cells, astrocytes microglia. These changes contribute dysregulation neural circuits involved reward stress, perpetuating alcohol-seeking behavior relapse. This review delves into how chronic exposure affects CeA, contributing pathophysiology AUD. By focusing on impact cell activation, aims elucidate mechanisms which neuroinflammation influences alcohol-related providing comprehensive overview current state research, identifies potential targets Understanding complex interplay between behaviors may pave way more effective improved outcomes individuals struggling

Language: Английский

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