Altered fear circuits in 5-HT1A receptor KO mice

The study of genetically altered mice has been used successfully to determine the influence of different neurotransmitter receptors on fear and anxiety. Mice with a genetic deletion of the serotonin 1A receptor (5-HT1AR knockout [KO]) have been shown to be more fearful in a number of behavioral conflict tests, confirming the important role of this receptor in modulating anxiety. Factor analysis of the behavior of WT and 5-HT1AR KO mice in the open field test shows that locomotion and anxiety measures segregate independently, supporting the idea that the anxious behavior of the KO mice is not the result of altered locomotion. KO mice also show increased anxiety in the novelty-suppressed feeding task, which differs from the other conflict tests in the motivational drive of the animals. In response to a discrete aversive stimulus, foot shock, the KO mice show increased freezing and increased tachycardia. However, activation of the hypothalamic–pituitary–adrenal axis in response to stress appears to be slightly blunted in the KO animals. Together, these data support the idea that the 5-HT1AR modulates an important fear circuit in the brain. The dual function of the 5-HT1AR as both a presynaptic autoreceptor, negatively regulating serotonin activity, and a postsynaptic heteroreceptor, inhibiting the activity of nonserotonergic neurons in forebrain structures, has complicated interpretation of the anxious phenotype of these KO mice. A more complete understanding of the function of the 5-HT1AR awaits further study of its role in behaving animals using tissue-specific antagonists and novel transgenic mice with tissue-specific expression of the receptor.