5HT2a Receptors – a New Target for Depression?

Cortical 5HT2A receptors are largely expressed in layer 5 pyramidal neurons and gate top-down inputs to local cortical microcircuits. Their number is increased in some people with depression, and blockade of these receptors partly explains the augmenting action of atypical antipsychotics. Agonists at these receptors—the psychedelic drugs psilocybin and LSD—profoundly reduce brain activity, especially in regions that highly express the 5HT2A receptor such as the default mode network (DMN). Since the DMN is overactive in depression, this reduction may explain improvements in mood that users of psychedelics often report. A study of psilocybin in resistant depression has been funded by the UK MRC and will start in early 2015.

Study at a glance

Abstract

Cortical 5HT2A receptors are largely expressed in layer 5 pyramidal neurons and appear to play a pivotal role in brain function in that they gate top-down descending inputs to local cortical microcircuits. There is evidence that they may play a role in depression in that the number of these receptors is increased in some people with depression and the augmenting action of atypical antipsychotics in depression is thought to be – at least in part – due to blockade of these receptors. We have explored this possibility by studying the effects of agonists at these receptors – the psychedelic druds psilocybin and LSD. We found they had profound effects to reduce brain activity particularly in regions that higly express the 5HT2A receptor such as the default mode network [DMN]. As this region is overactive in depression this may explain the improvements in mood that users of psychedelic often report. Based on these findings a study of psilocybin in resistant depression has been funded by the UK MRC and will start in early 2015.