title: Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder.
abstract: Post-traumatic stress disorder (PTSD) is a severely disabling anxiety disorder that may occur following exposure to a serious traumatic event. It is a psychiatric condition that can afflict anyone who has experienced a life-threatening or violent event. Previous studies have shown that changes in 18 kDa translocator protein (TSPO) expression (or function), a promising target for treating neurological disorders without benzodiazepine-like side effects, may correlate with PTSD. However, few studies have investigated the anti-PTSD effects of TSPO ligands. AC-5216, a ligand for TSPO, induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether AC-5216 ameliorates PTSD behavior in mice. Following the training session consisting of exposure to inescapable electric foot shocks, animals were administered AC-5216 daily during the behavioral assessments, i.e., situational reminders (SRs), the open field (OF) test, the elevated plus-maze (EPM) test, and the staircase test (ST). The results indicated that exposure to foot shocks induced long-term behavioral deficiencies in the mice, including freezing and anxiety-like behavior, which were significantly ameliorated by repeated treatment with AC-5216 but without any effect on spontaneous locomotor activity or body weight. In summary, this study demonstrated the anti-PTSD effects of AC-5216 treatment, suggesting that TSPO may represent a therapeutic target for anti-PTSD drug discovery and that TSPO ligands may be a promising new class of drugs for the future treatment of PTSD.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zhi-Kun
authors.initials: ZK
authors.lastname: Qiu
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Chen
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: Liu
authors.forename: Tian-Yue
authors.initials: TY
authors.lastname: Mi
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Ri-Fang
authors.initials: RF
authors.lastname: Yang
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Xu
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001526:Behavioral Symptoms / Q000188:drug therapy* / Q000523:psychology; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D046353:Immobility Response, Tonic / Q000187:drug effects; D008024:Ligands; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D018079:Receptors, GABA / Q000187:drug effects*; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000523:psychology
chemical_list: D014151:Anti-Anxiety Agents; C463819:Bzrp protein, mouse; D008024:Ligands; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D018079:Receptors, GABA
keywords: 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; 18kDa translocator protein; 18kDa translocator protein (TSPO); AC-5216; ANOVA; Allopregnanolone; CBR; CNS; EPM; Freezing behavior; GABA(A); HPA; IMM; N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide; OF; OMM; PK11195; PTSD; Post-traumatic stress disorder (PTSD); SBSSs; SPS; SRs; SSRIs; ST; Ser; TSPO; analysis of variance; central benzodiazepine receptor; central nervous system; elevated plus-maze; gamma-amino-butyric acid type A receptor; hypothalamic–pituitary–adrenal; inner mitochondrial membrane; open field; outer mitochondrial membrane; post-traumatic stress disorder; selective brain steroidogenic stimulants; selective serotonin reuptake inhibitors; sertraline; single prolonged stress; situational reminders; staircase test