Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice

J Psychopharmacol. 2010 May;24(5):733-43. doi: 10.1177/0269881109103091. Epub 2009 Apr 3.

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

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

Substances

  • Anti-Anxiety Agents
  • Antidepressive Agents
  • GABA Agonists
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Nipecotic Acids
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Receptors, Mineralocorticoid
  • Receptors, Steroid
  • Slc6a1 protein, mouse
  • Arginine Vasopressin
  • Corticotropin-Releasing Hormone
  • Corticosterone
  • Tiagabine