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.
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.
Thoeringer
C K
CK
Max Planck Institute of Psychiatry, Munich, Germany. thoeringer@mpipsykl.mpg.de
Erhardt
A
A
Sillaber
I
I
Mueller
M B
MB
Ohl
F
F
Holsboer
F
F
Keck
M E
ME
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000097:blood / Q000188:drug therapy*; D001127:Arginine Vasopressin / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000097:blood / Q000188:drug therapy*; D018755:GABA Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D000078308:Tiagabine
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; C493414:Slc6a1 protein, mouse; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D000078308:Tiagabine