Is this mouse anxious? The difficulties of interpreting the effects of genetic action. Commentary on Belzung ‘The genetic basis of the pharmacological effects of anxiolytics’ and Olivier et al. ‘The 5-HT receptor knockout mouse

If you had to develop an anxiolytic compound, what would you do? Would you try to remedy the deficiencies of the available anxiolytics or would you go after something novel? To help you decide, you might reasonably look at the track record of both strategies and you might be a little disheartened to find that there is not much to choose between them; the drugs we have now are not that dissimilar to those we had thirty years ago in terms of their site of action and their side effects. Now, however, there is some optimism that it will be possible to improve on existing anxiolytics. Success has been due to the use of genetic approaches, the subject of the papers by Ž . Ž . Belzung 2001 and Olivier et al. 2001 . The problem has been that the -aminobutyric Ž . acid A GABA and serotonin receptors, which A constitute the site of action of many drugs prescribed for anxiety disorders, have many effects, due in part to the large number of receptor subtypes: GABA can be divided into seven families with A Ž . multiple isoforms 15 in total and there are at least 14 serotonin receptor subtypes. Sorting out which subtype does what has been extremely difficult, although the ability to delete a receptor component genetically or mutate one subtype into another provides a powerful tool. In theory the process is straightforward: mutate the receptor in the mouse and study the behaviour and pharmacology of the animal. Olivier and colleagues describe the results of such an experiment. Three groups simultaneously published the results Ž . of deleting the 5-hydroxytryptamine 1A 5-HT1A receptor and reported very similar findings: the knockout animals displayed behaviours consistent with an increase in fearfulness, indicating that the Ž 5-HT receptor mediates anxiety responses Heisler 1A . et al., 1998; Parks et al., 1998; Ramboz et al., 1998 . Belzung describes the results of two groups showing that the sedative action of benzodiazepines is mediated mainly through the -subtype of the GABA 1 A Ž . receptor Low et al., 2000; McKernan et al., 2000 . However, results of knockout experiments are not always so clear-cut and the focus of both reviews is in trying to explain the inconsistencies of the genetic data. It is important to realize that the same knockout can be created in different genetic backgrounds; not only are there differences in the 129 strains commonly used for constructing the knockouts, but the mutation can also be bred on to different inbred strains. The effects of strain background have been Ž . known for some time Gerlai, 1996 and can be impressive. For example, the deletion of the epidermal growth factor receptor, important for development and tissue differentiation, led to death within the first few days of gestation on a CF-1 background, but on a CD-1 background went to full-term and Ž . lived for up to three weeks Threadgill et al., 1995 . Olivier and colleagues discuss what appears to be a similar problem. The 5-HT receptor knockout, on a Swiss 1A Webster background, is insensitive to the anxiolytic Ž . effect of diazepam Sibille et al., 2000 , suggesting some interesting mechanisms for the phenotype of the knockout. However, when Olivier and colleagues