Pharmacopsychiatry 2009; 42 - A149
DOI: 10.1055/s-0029-1240221

Forced swim-test-related antidepressant effects depend on P-glycoprotein expression in the Blood-Brain-Barrier

U Schmitt 1, Y Schoenfelder 1, L Karlsson 2, FC Kugelberg 3, F Bengtsson 2, C Hiemke 1
  • 1Department of Psychiatry and Psychotherapeutics, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
  • 2Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Sweden
  • 3Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden

Multi Drug Resistance carriers in the Blood-Brain-Barrier (BBB) protect from xenobiotic-induced tissue damage. Of all of the efflux pumps of the BBB p-glycoprotein (P-gp) handles the largest fraction of drugs. Besides transport of exogenous substances, P-gp is involved in the modulation of the hypothalamic-pituitary-adrenocortical (HPA) system by transporting corticosterone, too. We investigated the role of P-gp in the forced swim test on anti-depressant effects. P-gp k.o. mice (mdr1a/b -/-) were compared to wildtype FVB/N in the 2-day version of the forced swim test. Mice were treated with either saline (1ml, 0.9%), venlafaxine (10mg/kg), citalopram (10mg/kg) or duloxetine (10mg/kg) 30min before testing at day 2. Immobility of the mice was measured by an automatic computer based system (EthoVision®XT 5.1, Noldus). On day one knockout mice displayed less immobility compared to wildtype mice. Concerning to anti-depressant treatment immobility time was reduced in wildtype mice independent of the antidepressant used. In knockout mice however, no effect of any antidepressant treatment on immobility was detectable. These results gave strong evidence that substance transport by P-gp plays a role for stress response in the task. Defined anti-depressant-related behavioral changes seemed to be based on an intact BBB. Thus anti-depressant effectiveness displayed by the forced swim test reflects drug-induced changes on the HPA axis regulated by P-gp dependent corticosterone transport.