Different drugs that activate the same serotonin receptor (5-HT2AR) can produce distinct patterns of gene expression in the brain, which correspond to different behavioral effects. The hallucinogens DOI and LSD triggered a head-twitch response in mice and produced similar changes in the somatosensory cortex transcriptome, while the nonhallucinogenic drug lisuride did not cause this behavior and generated a different transcriptome fingerprint. These effects were absent in mice lacking the 5-HT2AR, confirming the receptor's role. The findings suggest that drugs acting at the same receptor can induce unique cellular response patterns in the living brain, detectable through transcriptome analysis.
Psilocybin activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). This activation is more pronounced in female mice and depends on serotonergic 5-HT2A and 5-HT2C receptors. The 5-HT2A receptor effects involve direct post-synaptic depolarization of CRHPVN neurons and increased presynaptic glutamate release. Psilocybin also alters how CRHPVN neurons respond to environmental changes, leading to a surprising decrease in activity that contrasts with typical stress responses. This context-specific modulation may be a key mechanism for recalibrating maladaptive stress reactivity, supporting the influence of setting on the psychedelic experience.