Serotonin 1 A auto‐receptors are not sufficient to modulate anxiety in mice

Abstract The neurotransmitter serotonin plays an important role in modulating diverse behavioral traits. Mice lacking the serotonin 1 A receptor ( H tr1a) show elevated avoidance of novel open spaces, suggesting that it has a role in modulating anxiety behavior. Htr1a is a G αi ‐coupled G ‐protein‐coupled receptor expressed on serotonin neurons (auto‐receptor), where it mediates negative feedback of serotonin neuron firing. Htr1a is also expressed on non‐serotonin neurons (hetero‐receptor) in diverse brain regions, where it mediates an inhibitory effect of serotonin on neuronal activity. Debate exists about which of these receptor populations is responsible for the modulatory effects of H tr1a on anxiety. Studies using tissue‐specific transgenic expression have suggested that forebrain Htr1a hetero‐receptors are sufficient to restore normal anxiety behavior to H tr1a knockout mice. At the same time, experiments using tissue‐specific transgenic suppression of H tr1a expression have demonstrated that H tr1a auto‐receptors, but not forebrain hetero‐receptors, are necessary for normal anxiety behavior. One interpretation of these data is that multiple H tr1a receptor populations are involved in modulating anxiety. Here, we aimed to test this hypothesis by determining whether H tr1a auto‐receptors are sufficient to restore normal anxiety to H tr1a knockout animals. Transgenic mice expressing H tr1a under the control of the tryptophan hydroxylase 2 ( T ph2 ) promoter showed restored H tr1a‐mediated serotonin negative feedback and hypothermia, but anxiety behavior indistinguishable from that of knockout mice. These data show that, in the absence of H tr1a hetero‐receptors, auto‐receptors are unable to have an impact on anxiety. When combined with previous data, these findings support the hypothesis that H tr1a auto‐receptors are necessary, but not sufficient, to modulate anxiety.