ABSTRACT
Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalamic-pituitary-adrenocortical (HPA) system regulation. GAT-1 blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus and of hippocampal steroid receptors. This data indicate that both acute and long-term anxiolytic and antidepressant-like properties of brain GAT-1 inhibition coincide with a reduction in HPA system activity in mice.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Anxiety/drug therapy , Depression/drug therapy , Hypothalamo-Hypophyseal System/drug effects , Nipecotic Acids/therapeutic use , Pituitary-Adrenal System/drug effects , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/administration & dosage , Antidepressive Agents/pharmacology , Anxiety/blood , Arginine Vasopressin/genetics , Arginine Vasopressin/metabolism , Corticosterone/blood , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Depression/blood , GABA Agonists/administration & dosage , GABA Agonists/therapeutic use , GABA Plasma Membrane Transport Proteins , GABA Uptake Inhibitors , Gene Expression Regulation/drug effects , Hippocampus/metabolism , Male , Mice , Mice, Inbred C57BL , Nipecotic Acids/administration & dosage , Nipecotic Acids/pharmacology , Paraventricular Hypothalamic Nucleus/metabolism , RNA, Messenger/metabolism , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/genetics , Receptors, Mineralocorticoid/metabolism , Receptors, Steroid/genetics , Receptors, Steroid/metabolism , TiagabineABSTRACT
Chronic bronchitis is associated with airways obstruction and inflammation. In order to determine whether aerosolized beclomethasone can modulate airway inflammation and diminish airway obstruction, subjects with chronic bronchitis performed spirometry and underwent bronchoalveolar lavage (BAL) before and after receiving 6 wk of therapy (five puffs four times a day) with either aerosolized beclomethasone (n = 20) or placebo (n = 10) in a double-blinded, randomized fashion. All subjects received aerosolized albuterol before each use of the study medications. Before BAL, the airways were visually assessed for the appearance of inflammation and assigned a score, the bronchitis index. BAL was performed by instilling five 20-ml aliquots of saline into each of three sites and pooling and separately analyzing the returns from the first aliquots to yield a "bronchial sample." The bronchial lavages were repeated in an additional three sites to increase the volume of fluid available for analysis. The fluid was prepared for cytologic examination by cytocentrifugation. Albumin (as a measure of epithelium permeability) and lactoferrin and lysozyme (as measures of serous cell activity) were measured in unconcentrated BAL fluid by enzyme-linked immunosorbent assay, and concentrations in epithelial lining fluid were estimated using urea as an internal marker for dilution. After treatment, the beclomethasone group, but not the placebo group, showed improvement in FVC (p = 0.02), FEV1 (p = 0.002), and 25 to 75% forced expiratory flow (p = 0.006). Associated with the improvement in spirometry, the bronchitis index fell (13.5 +/- 1.0 versus 10.75 +/- 1.1, p = 0.02) in the beclomethasone-treated group, but not the placebo-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)