5-HT1A receptor knockout mouse as a genetic model of anxiety

Low levels of the serotonin(1A) (5-HT(1A)) receptor have been repeatedly found in mood and anxiety disorders. Stress often exacerbates psychiatric disease and can also reduce 5-HT(1A) receptor levels. When receptor deficiency was produced in mice by genetic knockout, an anxiety-like phenotype was observed. Anxiety in mice is defined as a high level of avoidance of novel and unfamiliar environment and increased fear reaction. Other aspects of anxiety such as autonomic activation, increased stress responsiveness, and neuroendocrine abnormalities have also been described in receptor knockout mice. These data indicate that 5-HT(1A) receptor knockout mice represent a genetic animal model of anxiety with both construct and face validities. Although the core phenotype of anxiety can be reproduced in knockout mice in various inbred and outbred backgrounds, abnormalities in 5-HT dynamics and resistance to the anxiolitic drug diazepam have been seen in one but not on other genetic backgrounds. This indicates that while the development of anxiety is an invariable consequence of receptor deficit, other features induced by receptor loss are strongly modulated by other gene(s). Strain-dependent variability within the core phenotype does not diminish the value of 5-HT(1A) receptor knockout mice as a model of anxiety. Indeed, it is consistent with the manifestation of anxiety in genetically heterogeneous human population.