ABSTRACT
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.
Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Oligopeptides/pharmacology , Stress Disorders, Post-Traumatic/drug therapy , Adrenocorticotropic Hormone/blood , Animals , Anti-Anxiety Agents/administration & dosage , 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 , Pituitary-Adrenal System/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Stress Disorders, Post-Traumatic/physiopathologyABSTRACT
OBJECTIVE: To study the cardiovascular effect of selective orexin-1 receptor (OX1R) antagonist SB408124 in anesthetized rats and explore the underlying mechanism by using intracerebroventricular (ICV) microinjection combined with immunohistochemical assay. METHODS: The changes of mean arterial blood pressure (MAP) and heart rate (HR) of male Sprague-Dawley rats were recorded during ICV microinjection of SB408124 with or without pretreatment of atropine methyl nitrate or hexamethonium bromide. Furthermore, tyrosine hydroxylase (TH) immunopositive neurons in the rostral ventrolateral medulla (RVLM) of the rat were detected with immunohistochemical assay after ICV microinjection of SB408124. RESULTS: ICV administration of SB408124 resulted in a significant decrease in MAP in anesthetized rats, which was accompanied with a mild decrease in HR. The cardiovascular responses elicited by SB408124 were not abolished by pretreatment of atropine methyl nitrate whereas fully abolished by pretreatment of hexamethonium bromide. The number of TH-immunopositive neurons in rat RVLM were significantly decreased following ICV administration of SB408124. CONCLUSION: ICV microinjection of selective OX1R antagonist SB408124 can cause decreases of MAP and HR mediated by inhibiting sympathetic activity in anesthetized rats.
Subject(s)
Blood Pressure/drug effects , Heart Rate/drug effects , Phenylurea Compounds/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Animals , Male , Orexin Receptors , Phenylurea Compounds/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
The administration of certain fluoroquinolone antibacterials has recently been linked to QT interval prolongation, raising the clinical concerns over the cardiotoxicity of these agents. In this study, the effects of a novel fluoroquinolone, antofloxacin hydrochloride (AX) on human-ether-à-go-go-related gene (HERG) encoding potassium channels and the biophysical mechanisms of drug action were performed with whole-cell patch-clamp technique in transiently transfected HEK293 cells. The administration of AX caused voltage- and time-dependent inhibition of HERG K+ current (I(HERG/MiRP1)) in a concentration-dependent manner but did not markedly modify the properties of channel kinetics, including activation, inactivation, deactivation and recovery from inactivation as well. In comparison with sparfloxacin (SPX), levofloxacin lactate (LVFX), the potency of AX to inhibit HERG tail currents was the least one, with an IC(50) value of 460.37 microM. By contrast, SPX was the most potent compound, displaying an IC(50) value of 2.69 microM whereas LVFX showed modest potency, with an IC(50) value of 43.86 microM, respectively. Taken together, our data suggest that AX only causes a minor reduction of I(HERG/MiRP1) at the estimated free plasma level.
