Serotonin receptor knockouts: A moody subject

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is believed to play a significant role in determining one’s emotional state. Indeed, serotonergic synapses are sites of action for a number of mood-altering drugs, including the now-legendary antidepressant Prozac (fluoxetine) (1). As a result, there has been tremendous interest in identifying molecular components of the serotonergic system, including cell surface receptors and transporters, and understanding whether and how these proteins contribute to the regulation of mood and emotion. This quest is driven, in part, by the possibility that behavioral disorders, such as depression or anxiety, may be linked to deficits in one or more components of this signaling system. Such information could, in turn, focus attention on specific targets for the development of novel drugs with which to treat psychiatric disorders. In the case of serotonin, this is a particularly challenging goal because the system is quite complex, consisting of at least 14 distinct receptor subtypes (2). Nevertheless, pharmacological and physiological studies have highlighted a subset of 5-HT receptor subtypes worthy of more immediate genetic analysis. One of these, the 5-HT1A receptor, is the focus of two studies by Ramboz et al. (3) and Heisler et al. (4) in recent issues of the Proceedings. These groups used gene “knockout” methods to generate mouse lines lacking 5-HT1A receptors so that they could assess the effects of receptor ablation on behavior, using models of anxiety and depression.