New approach to modulating serotonin signalling in the brain

Serotonin (aka 5-HT) signalling is essential in the brain for normal physiological processes, including appetite control. Misfunctioning of the serotonin system has been implicated in a number of psychiatric disorders, including addiction, depression and – perhaps unsurprisingly – eating disorders. It is clear then why it would be beneficial to be able to modulate signalling through serotonin receptors, which are found throughout the brain, but especially in the limbic-corticostriatal circuits, which are associated with reward and motivation.

A team of researchers from the University of Texas Medical Branch and the University of Houston have done just this, identifying a new drug binding site on the 5-HT_2C receptor. An endogenous molecule called PTEN binds to this site, located away from the serotonin binding site, inhibiting serotonin signalling allosterically. The researchers have identified another molecule called 3LF4 – actually a fragment of the 5-HT_2C receptor itself – which binds competitively to PTEN and prevents it from binding to the receptor.

The group demonstrated that 5-HT_2C­ signalling was significantly enhanced by application of 3LF4 both in vitro and in cell culture. These results were supported by behavioural studies in rats treated with 3LF4. It is thought that inhibiting formation of the PTEN–5-HT_2C receptor complex in this way lifts PTEN’s inhibition of the serotonin receptor. It was also shown that 3LF4 has no effect on another serotonin receptor, 5-HT_2A, suggesting that it is selective for the 5-HT_2C subtype.

Following these encouraging results, the team were able to prune 3LF4 down to make a smaller peptide with a similar action and identified the regions that are crucial for its interaction with PTEN. They plan to use these elements to build further molecules with improved activity. These may have therapeutic value in a number of disorders, such as addictions, where patients seem to benefit from increased serotonin signalling.