GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations.
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.


CONCLUSIONS
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.
Division of Biosciences, The Ohio State University, College of Dentistry, Columbus, OH 43210, USA; Facultad de Odontología, Universidad de Costa Rica, San Pedro, San José 11501-2060, Costa Rica. Electronic address: ramirezchan.1@buckeyemail.osu.edu.
Karol
K
Ramirez
Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, Columbus, OH 43212, USA. Electronic address: niraula.1@osu.edu.
Anzela
A
Niraula
Division of Biosciences, The Ohio State University, College of Dentistry, Columbus, OH 43210, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA; Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA. Electronic address: sheridan.1@osu.edu.
John F
JF
Sheridan
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000209:etiology / Q000276:immunology*; D001522:Behavior, Animal / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000276:immunology*; D039481:CD11b Antigen / Q000378:metabolism; D002998:Clonazepam / Q000008:administration & dosage*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D018757:GABA Modulators / Q000008:administration & dosage*; D006098:Granulocytes / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology; D007031:Hypothalamus / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D008140:Lorazepam / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013163:Splenomegaly / Q000209:etiology / Q000517:prevention & control; D013315:Stress, Psychological / Q000150:complications / Q000276:immunology*
D014151:Anti-Anxiety Agents; D039481:CD11b Antigen; D018757:GABA Modulators; D015850:Interleukin-6; D012333:RNA, Messenger; D002998:Clonazepam; D003346:Corticotropin-Releasing Hormone; D008140:Lorazepam; D003345:Corticosterone
Anxiety-like behavior; Benzodiazepines; Microglia; Psychosocial stress; Social avoidance; Social defeat