Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex
Abstract
Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.
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Psychedelics do not lead to addiction in humans, and the rapid tolerance effects that follow psychedelic administration further limits their abuse potential.
“Furthermore, although some addictive potential has been demonstrated for classical and non-classical psychedelics on rat models (161), psychedelics do not lead to addiction in humans (162), and the rapid tolerance effects that follow psychedelic administration further limits their abuse potential (163, 164).”
From Examining the Potential Synergistic Effects Between Mindfulness Training and Psychedelic-Assisted Therapy (2021) · cites this paper as [164]
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SANTOS, R. G. D., & Hallak, J. E. C. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-18496-3.00015-x
- Authors
- Gresch, P. J., Smith, R. L., Barrett, R. J., & Sanders-Bush, E.
- Affiliations
- Vanderbilt University (US)
- United States Department of Veterans Affairs (US)
- Venue
- Neuropsychopharmacology
- Published
- 2005-03-09
- Volume
- 30
- Issue
- 9
- Pages
- 1693-1702
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2012834083
- Cited by
- 62
- References
- 43
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 3 · 2012: 2
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32da015165-02)
- National Institute on Drug Abuse (DA-05181, DA15165, R01DA005181)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- lysergic acid diethylamide, 5-HT2A receptor, drug discrimination, hallucinogens, G protein coupling, medial prefrontal cortex, anterior cingulate cortex, discriminative stimulus effects, chronic drug exposure, receptor down-regulation
- MeSH terms
- Amphetamines, Analysis of Variance, Animals, Autoradiography, Behavior, Animal, Cerebral Cortex, Diagnostic Imaging, Drug Interactions, Drug Tolerance, Fluorobenzenes, Hallucinogens, Indoles, Iodine Isotopes, Lysergic Acid Diethylamide, Male, Piperidines, Protein Binding, Pyridines, Serotonin Antagonists, Sulfur Isotopes, Time Factors, Signal Transduction, Guanosine 5'-O-(3-Thiotriphosphate), Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A, Rats
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