5-HT2A receptor

The 5-HT_2A receptor is a subtype of the 5-HT₂ receptor that belongs to the serotonin receptor family and functions as a G protein-coupled receptor (GPCR). It is a cell surface receptor that activates multiple intracellular signalling cascades. Like all 5-HT₂ receptors, the 5-HT_2A receptor is coupled to the G_q/G₁₁ signaling pathway. It is the primary excitatory receptor subtype among the serotonin-responsive GPCRs. The 5-HT_2A receptor was initially noted for its central role as the primary target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. It later regained research prominence when found to mediate, at least in part, the effects of many antipsychotic drugs, particularly atypical antipsychotics.

Downregulation of post-synaptic 5-HT_2A receptors is an adaptive response triggered by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics. Elevated 5-HT_2A receptor density has been observed in suicidal and otherwise depressed patients, suggesting that post-synaptic 5-HT_2A receptor overexpression may contribute to the pathogenesis of depression. Paradoxically, several 5-HT_2A receptor antagonists can also induce receptor downregulation. This effect may lead to reverse tolerance, rather than the expected development of tolerance. However, at least one antagonist has been shown to upregulate 5-HT_2A receptor expression, and a few others appear to have no effect on receptor levels. Nonetheless, such upregulation remains the exception rather than the rule.

Importantly, neither tolerance nor rebound has been observed in humans in relation to the slow-wave sleep (SWS)-promoting effects of 5-HT_2A antagonists.