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PMID: 14523084 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 23 ·No. 26 ·2003-10-01 ·Pages 8836-43

González-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC

Abstract

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

MeSH Terms
Animals Behavior, Animal/drug effects Cell Line Feasibility Studies Gene Expression/drug effects Gene Expression Profiling Hallucinogens/pharmacology Humans Kidney/cytology,drug effects,metabolism Mice Mice, Knockout Mice, Mutant Strains Oligonucleotide Array Sequence Analysis Receptor, Serotonin, 5-HT2A Receptors, Serotonin/drug effects,genetics Signal Transduction/drug effects,physiology Somatosensory Cortex/drug effects,metabolism Transcription, Genetic/drug effects
Chemicals
Hallucinogens Receptor, Serotonin, 5-HT2A Receptors, Serotonin
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
González-Maeso Javier
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Yuen Tony
Ebersole Barbara J
Wurmbach Elisa
Lira Alena
Zhou Mingming
Weisstaub Noelia
Hen Rene
Gingrich Jay A
Sealfon Stuart C
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2003-10-01
Pages
8836-43
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6740401
Subset
IM
Grants
NIDA NIH HHS · P01 DA012923 · United States
NIDA NIH HHS · P01-DA12923 · United States
External Links
PubMed source PMC Full Text View journal details
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