The scaffolding protein PSD-95, known for organizing glutamate receptors at synapses, also critically regulates serotonin 5-HT2A and 5-HT2C receptors. In mice lacking PSD-95, these serotonin receptors show reduced expression, abnormal distribution in dendrites, and impaired signaling. Hallucinogen-induced behaviors and the effects of atypical antipsychotics that target these receptors are disrupted. PSD-95 is essential for normal serotonergic receptor function, expanding its role beyond glutamate signaling.
Substituted tryptamines show varying potency and selectivity at serotonin receptors and the serotonin transporter. Several compounds, including 5-MeO-DMT and 5-MeO-tryptamine, are potent 5-HT2AR agonists, while others like 5-MeO-NMT and bufotenine have lower activity. At 5-HT2CR, 5-MeO-DMT and 5-MeO-tryptamine are also potent, but bufotenine is inactive. Most tryptamines have weak or no activity at 5-HT1AR and the serotonin transporter. The findings indicate that the 5-methoxy substitution enhances 5-HT2AR and 5-HT2CR potency, while the N,N-dimethyl group is important for high efficacy.