Anxiolytic effects of GLYX-13 in animal models of posttraumatic stress disorder-like behavior

• Published in: Journal of psychopharmacology (Oxford) Vol. 30; no. 9; p. 913
• Main Authors: Jin, Zeng-Liang, Liu, Jin-Xu, Liu, Xu, Zhang, Li-Ming, Ran, Yu-Hua, Zheng, Yuan-Yuan, Tang, Yu, Li, Yun-Feng, Xiong, Jie
• Format: Journal Article
• Language: English
• Published: United States 01.09.2016
• Subjects: Adrenocorticotropic Hormone - blood; Animals; Anti-Anxiety Agents - administration & dosage; Anti-Anxiety Agents - pharmacology; Anxiety - drug therapy; Behavior, Animal - drug effects; Corticosterone - blood; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus - metabolism; Hypothalamo-Hypophyseal System - metabolism; Male; Mice; Mice, Inbred ICR; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Pituitary-Adrenal System - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid - metabolism; Stress Disorders, Post-Traumatic - drug therapy; Stress Disorders, Post-Traumatic - physiopathology; GLYX-13; HPA axis; Posttraumatic stress disorder; glucocorticoid receptors; electric foot shock
• ISSN: 1461-7285
• DOI: 10.1177/0269881116645298

In the present study, we investigated the effectiveness of GLYX-13, an NMDA receptor glycine site functional partial agonist, to alleviate the enhanced anxiety and fear response in both a mouse and rat model of stress-induced behavioral changes that might be relevant to posttraumatic stress disorder (PTSD). Studies over the last decades have suggested that the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in stress-related disease. Herein, we used these animal models to further investigate the effect of GLYX-13 on the stress hormone levels and glucocorticoid receptor (GR) expression. We found that exposure to foot shock induced long-lasting behavioral deficiencies in mice, including freezing and anxiety-like behaviors, that were significantly ameliorated by the long-term administration of GLYX-13 (5 or 10 mg/kg). Our enzyme-linked immunosorbent assay results showed that long-term administration of GLYX-13 at behaviorally effective doses (5 or 10 mg/kg) significantly decreased the elevated serum levels of both corticosterone and its upstream stress hormone adrenocorticotropic hormone in rats subjected to the TDS procedure. These results suggest that GLYX-13 exerts a therapeutic effect on PTSD-like stress responding that is accompanied by (or associated with) modulation of the HPA axis, including inhibition of stress hormone levels and upregulation of hippocampal GR expression.