Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.

Dysfunctions of the serotonergic system have been implicated in a number of psychiatric disorders including depression, anxiety and disorders of impulse control. To model these disorders we have generated mice with altered serotonergic systems. Specifically, we have created mice that lack or express reduced levels of two serotonin receptors: 5-HT1A and 5-HT1B receptors. These receptors are localized both on serotonergic neurons where they act as autoreceptors and on non-serotonergic neurons. As a result, the 5-HT1A and 5-HT1B receptors control the tone of the serotonergic system and mediate some of the postsynaptic effects of serotonin. Agonists of these receptors are currently used in the treatment of migraine and anxiety disorders. Mice lacking these receptors develop, feed, and breed normally and do not display any obvious abnormalities. However, when analyzed in a number of behavioral paradigms, the 5-HT1A and 5-HT1B knockout mice display a number of contrasting phenotypes. While the 5-HT1B knockout mice are more aggressive, more reactive, and less anxious than the wild-types, the 5-HT1A knockouts are less reactive, more anxious, and possibly less aggressive than the wild-types. We are currently investigating with tissue-specific knockout mice which neural circuits are responsible for these phenotypes.