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.
Classic psychedelics like DOI cause lasting changes in experience and show promise for treating depression. In the medial prefrontal cortex of male mice, DOI reduced low-frequency brain waves during rest, preventing the usual synchronization that occurs in less active states. It also increased gamma activity and suppressed fast-spiking neurons both during active and rest periods. These results suggest that DOI induces persistent desynchronization in the medial prefrontal cortex, which may contribute to the longer-lasting effects of psychedelics on brain plasticity and their therapeutic properties.