{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:03:57Z","timestamp":1768518237333,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,12]]},"group-title":"Neuroscience","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T00:00:00Z","timestamp":1728691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The distinct subjective effects that define psychedelics such as LSD, psilocybin or DOI as drug class are causally linked to activation of the serotonin 2A receptor (5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R). However, some aspects of 5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from non-psychedelic 5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R engagement of the canonical G\n                  <jats:sub>q\/11<\/jats:sub>\n                  pathway in native tissue. This non-radioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP\n                  <jats:sub>1<\/jats:sub>\n                  ) in the mouse brain. The specificity of this method was assessed by comparing IP\n                  <jats:sub>1<\/jats:sub>\n                  levels in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R-KO animals compared to other brain regions, namely striatum and cerebellum. Furthermore, we encountered that head-twitch response (HTR) counts and IP\n                  <jats:sub>1<\/jats:sub>\n                  in the frontal cortex were correlated. We observed that IP\n                  <jats:sub>1<\/jats:sub>\n                  levels in frontal cortex homogenates from mice treated with LSD and lisuride vary in magnitude, consistent with LSD\u2019s 5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R agonism and psychedelic nature, and lisuride\u2019s lack thereof. MDMA evoked an increase of IP\n                  <jats:sub>1<\/jats:sub>\n                  signal in the frontal cortex that were not matched by the serotonin precursor 5-HTP or the serotonin reuptake inhibitor fluoxetine. We attribute differences in the readout primarily to the indirect stimulation of 5-HT\n                  <jats:sub>2A<\/jats:sub>\n                  R by MDMA via serotonin release from its presynaptic terminals. This methodology enables capturing a snapshot of IP\n                  <jats:sub>1<\/jats:sub>\n                  turnover in the mouse brain that can provide mechanistic insights in the study of psychedelics and other serotonergic agents pharmacodynamics.\n                <\/jats:p>","DOI":"10.1101\/2024.10.11.617861","type":"posted-content","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T23:55:17Z","timestamp":1728777317000},"source":"Crossref","is-referenced-by-count":0,"title":["Snapshot of 5-HT\n                  <sub>2A<\/sub>\n                  receptor activation in the mouse brain via IP\n                  <sub>1<\/sub>\n                  detection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-4922","authenticated-orcid":false,"given":"Mario","family":"de la Fuente Revenga","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3105-3204","authenticated-orcid":false,"given":"Javier","family":"Gonz\u00e1lez-Maeso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024101601550737000_2024.10.11.617861v1.1","doi-asserted-by":"publisher","DOI":"10.1080\/02791072.2021.2022254"},{"key":"2024101601550737000_2024.10.11.617861v1.2","doi-asserted-by":"crossref","unstructured":"Kometer, M. ; Schmidt, A. ; J\u00e4ncke, L. ; Vollenweider, F. X . Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on \u03b1 Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations. 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