Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models.

Clinical studies have suggested the involvement of 5-HT 1 A receptors in anxiety and depressive disorders because partial 5-HT 1 A receptor agonists such as buspirone are therapeutic. The present review considers evidencefrom genetic animal models that support a role for 5-HT 1 A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT 1 A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT 1 A agonist. Although the HDS rats do exhibit elevations in 5-HT 1 A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT 1 A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT 1 A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT 1 A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.