title: Midazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis.
abstract: Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been shown that the 18 kDa translocator protein (TSPO) may be correlated with PTSD and that the TSPO ligand improved the behavioral deficits in a mouse model of PTSD. Midazolam, a ligand for TSPO and central benzodiazepine receptor (CBR), induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether midazolam ameliorates PTSD behavior in rats as assessed by the single prolonged stress (SPS) model. The SPS rats received daily Sertraline (Ser) (15 mg/kg, i.p.) [corrected] and midazolam (0.125, 0.25, 0.5, and 1 mg/kg, i.p.) [corrected] during the exposure to SPS and behavioral assessments, which included the open field (OF) test, the contextual fear paradigm (CFP), and the elevated plus-maze (EPM). The results showed that, like Ser (15 mg/kg, i.p.) [corrected], midazolam (0.25 and 0.5 mg/kg, i.p.) [corrected] significantly reversed the behavioral deficiencies of the SPS rats, including PTSD-associated freezing and anxiety-like behavior but not the effects on spontaneous locomotor activity. In addition, the anti-PTSD effects of midazolam (0.5 mg/kg, i.p.) [corrected] were antagonized by the TSPO antagonist PK11195 (3 mg/kg, i.p.), the CBR antagonist flumazenil (15 mg/kg, i.p.) [corrected] and the inhibitor of steroidogenic enzymes finasteride (30 mg/kg, i.p.) [corrected], which by themselves had no effect on PTSD-associated freezing and anxiety-like behavior. In summary, this study demonstrated that midazolam improves the behavioral deficits in the SPS model through dual TSPO and CBR and neurosteroidogenesis.
authors.affiliation: Department of Anesthesiology, Chinese PLA No. 306 Hospital, Beijing, P.R. China.
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Miao
authors.affiliation: Department of Anesthesiology, Beijing Military General Hospital of the PLA, Beijing, P.R. China.
authors.forename: Wen-Zhi
authors.initials: WZ
authors.lastname: Guo
authors.affiliation: Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Sanya, P.R. China.
authors.forename: Wen-Zhu
authors.initials: WZ
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology, Chinese PLA No. 306 Hospital, Beijing, P.R. China.
authors.forename: Wei-Wu
authors.initials: WW
authors.lastname: Fang
authors.affiliation: Department of Anesthesiology, Chinese PLA No. 306 Hospital, Beijing, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Chinese PLA No. 306 Hospital, Beijing, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Head and Neck Surgery of Otolaryngology, Chinese PLA No. 306 Hospital, Beijing, P.R. China.
authors.forename: Bao-Wei
authors.initials: BW
authors.lastname: Li
authors.affiliation: Department of Head and Neck Surgery of Otolaryngology, Chinese PLA No. 306 Hospital, Beijing, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, P.R. China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008874:Midazolam / Q000627:therapeutic use*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D020280:Sertraline / Q000627:therapeutic use; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D002352:Carrier Proteins; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D020280:Sertraline; D008874:Midazolam