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How Psychedelic or Hallucinogenic Drugs Work These experiments were very strong evidence that 5-HT2A receptor signaling was not generating a retrograde messenger. Different agonist ligands acting at the 5-HT2A receptor also can lead to different downstream gene expression patterns. González-Maeso et al. quantified concentration-dependent gene changes in response to various agonists in HEK-293 cells expressing the human 5-HT2A receptor, followed by examination of the in vivo gene expression responses in the mouse somatosensory cortex. Unexpectedly, however, these lesions led to increased density of cortical 5-HT2A receptors, a finding that would not be entirely consistent with presynaptic 5-HT2A receptor localization. Shi et al. examined agonist-induced desensitization of 5-HT2A receptors in the rat hypothalamic paraventricular nucleus with 1 mg/kg R-(−)-DOI. Treatment with R-(−)-DOI for either 4 or 7 days caused a significant approximately 50% decrease in high-affinity 5-HT2A bindin...