5-HT_2A receptor

The 5-HT_2A receptor is a subtype of the 5-HT₂ receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT_2A receptor is a cell surface receptor, but has several intracellular locations.

Like all 5-HT2 receptors, the 5-HT2A receptor is G_q/G₁₁-protein coupled. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT_2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones.

Downregulation of post-synaptic 5-HT_2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics. Suicidal and otherwise depressed patients have had more 5-HT_2A receptors than normal patients. These findings suggest that post-synaptic 5-HT_2A overdensity is involved in the pathogenesis of depression.

Paradoxical down-regulation of 5-HT_2A receptors can be observed with several 5-HT_2A antagonists. Thus, instead of tolerance, reverse-tolerance would be expected from 5-HT_2A antagonists. However, there is at least one antagonist at this site which has been shown to up-regulate 5-HT_2A receptors. Additionally, a couple of other antagonists may have no effect on 5-HT_2A receptor number. Nevertheless, upregulation is the exception rather than the rule. Neither tolerance nor rebound is observed in humans with regard to the slow-wave sleep (SWS) promoting effects of 5-HT_2A antagonists.