Behavioral and physiological mouse models for anxiety: effects of flesinoxan in 129S6/SvEvTac and C57BL/6J mice

Serotonin(1A) (5-HT1A) receptors are involved in anxiety. This study focuses on the role of genetic factors on the anxiety-related effects of 5-HT1A receptor stimulation using both a within subject design. The effects of 5-HT1A receptor activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related assays. These two strains were also selected because they are frequently used in gene-targeting studies. Mice were treated with the selective 5-HT1A receptor agonist flesinoxan (0-0.3-1.0-3.0 mg/kg s.c.) and tested in either the open-field activity test, the light-dark exploration test, or the stress-induced hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also decreased activity on several behavioral measures in B6 mice. Flesinoxan produced only minimal effects in the behavioral tests in the high-anxiety S6 strain. In contrast, the physiological hyperthermia response showed anxiolytic-like effects of flesinoxan in both strains. Our data indicate that the role of 5-HT1A receptor activation on anxiety-related responses is dependent on genetic background and selected paradigm used to assess anxiety. These findings indicate that it is critical to use a multi-level approach to develop mouse models for human diseases. In addition, the implication of such findings for studies on genetically modified mice is discussed. (C) 2004 Elsevier B.V All rights reserved.