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.
MeSH terms
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Animals
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Anti-Anxiety Agents / administration & dosage
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Anti-Anxiety Agents / pharmacology
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Anti-Anxiety Agents / therapeutic use*
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Antidepressive Agents / administration & dosage
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Antidepressive Agents / pharmacology
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Antidepressive Agents / therapeutic use*
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Anxiety / blood
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Anxiety / drug therapy*
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Arginine Vasopressin / genetics
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Arginine Vasopressin / metabolism
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Corticosterone / blood
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Corticotropin-Releasing Hormone / genetics
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Corticotropin-Releasing Hormone / metabolism
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Depression / blood
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Depression / drug therapy*
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GABA Agonists / administration & dosage
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GABA Agonists / therapeutic use
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GABA Plasma Membrane Transport Proteins
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GABA Uptake Inhibitors
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Gene Expression Regulation / drug effects
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Hippocampus / metabolism
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Hypothalamo-Hypophyseal System / drug effects*
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Male
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Mice
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Mice, Inbred C57BL
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Nipecotic Acids / administration & dosage
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Nipecotic Acids / pharmacology
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Nipecotic Acids / therapeutic use*
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Paraventricular Hypothalamic Nucleus / metabolism
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Pituitary-Adrenal System / drug effects*
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RNA, Messenger / metabolism
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism
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Receptors, Mineralocorticoid / genetics
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Receptors, Mineralocorticoid / metabolism
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism
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Tiagabine
Substances
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Anti-Anxiety Agents
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Antidepressive Agents
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GABA Agonists
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GABA Plasma Membrane Transport Proteins
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GABA Uptake Inhibitors
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Nipecotic Acids
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RNA, Messenger
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Receptors, Glucocorticoid
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Receptors, Mineralocorticoid
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Receptors, Steroid
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Slc6a1 protein, mouse
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Arginine Vasopressin
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Corticotropin-Releasing Hormone
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Corticosterone
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Tiagabine