GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations
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Objective Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b(+)/Ly6C(hi)) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD.Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD.Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b(+)/CD45(high)) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD.Conclusion These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.
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Psychosocial stress triggers generation of myeloid progenitor cells marked by CD11b+ and Ly6Chigh and leads to accumulation of macrophages (CD11b+ and CD45high) in the central nervous system, alongside increased IL-6 levels.
“Additionally, psychosocial stress triggers the generation of myeloid progenitor cells marked by CD11b+ and Ly6Chigh and leads to the accumulation of macrophages (CD11b+ and CD45high) in the central nervous system, alongside increased IL-6 levels [20].”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [20]
Interventions with noradrenergic receptor antagonists or GABAergic agonists prevent RSD-induced IL-6 increase, monocyte recruitment to the brain, and anxiety-like behavior.
“Interventions with noradrenergic receptor antagonist or GABAergic agonists prevented RSD-induced IL-6 increase, monocyte recruitment to the brain, and anxiety-like behavior following RSD [24, 25].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [24]
These morphological alterations were associated with the classical activation profile, characterized by the increased expression of antigen presentation molecule (MHCII), cell surface markers (TLR4 and CD14), and pro-inflammatory cytokines and chemokines (IL-1β, TNFα, IL-6, and CCL2).
“These morphological alterations were associated with the classical activation profile, characterized by the increased expression of antigen presentation molecule (MHCII), cell surface markers (TLR4 and CD14), and pro-inflammatory cytokines and chemokines (IL-1β, TNFα, IL-6, and CCL2) (Frank et al, 2007;Ramirez et al, 2016;Wohleb et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Ramirez et al, 2016
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Pro-inflammatory cytokines and psychotherapy in depression: Results from a randomized clinical trial
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Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology
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“Additionally, psychosocial stress triggers the generation of myeloid progenitor cells marked by CD11b + and Ly6C high and leads to the accumulation of macrophages (CD11b + and CD45 high ) in the central nervous system, alongside increased IL-6 levels [20].”
- Authors
- Ramirez, K., Niraula, A., & Sheridan, J. F.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- Corresponding author
- Sheridan, John F.
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 51
- Pages
- 154-168
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC4679551
- OpenAlex
- W1798878514
- Cited by
- 101
- References
- 78
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 12 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 9 · 2019: 11 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 1
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- NIH/NIMH (R01 MH097243-02, R01 MH093473-03)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- benzodiazepines, lorazepam, clonazepam, repeated social defeat, psychosocial stress, neuroinflammation, translocator protein (TSPO), GABAergic modulation, myeloid progenitor cells, monocyte trafficking, splenomegaly, inflammatory cytokines, anxiety-like behavior, depression-like behavior, corticosterone
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Bone Marrow, Brain, Clonazepam, Corticosterone, Corticotropin-Releasing Hormone, Granulocytes, Hematopoiesis, Hippocampus, Hypothalamus, Lorazepam, Male, Mice, Inbred C57BL, Monocytes, RNA, Messenger, Splenomegaly, Stress, Psychological, Anti-Anxiety Agents, Interleukin-6, Microglia, GABA Modulators, CD11b Antigen, Mice
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