PSD-95 Is Essential for Hallucinogen and Atypical Antipsychotic Drug Actions at Serotonin Receptors
Atheir I. Abbas, Prem N. Yadav, Wei-Dong Yao, Margaret I. Arbuckle, Seth G. N. Grant, Marc G. Caron, Bryan L. Roth
Journal of Neuroscience June 3, 2009 DOI: 10.1523/jneurosci.1090-09.2009 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Topics | Serotonin |
| Keywords | Postsynaptic density Postsynaptic potential Metabotropic receptor 5-HT Receptor Pharmacology Cell biology Metabotropic glutamate receptor Long-term depression Ampa receptor |
| Citations | 131 |
| Key findings | PSD-95 is essential for normal expression, dendritic targeting, and signaling of 5-HT2A and 5-HT2C serotonin receptors, and for mediating behavioral responses to hallucinogens and atypical antipsychotics. |
Abstract
Here, we report that postsynaptic density protein of 95 kDa (PSD-95), a postsynaptic density scaffolding protein, classically conceptualized as being essential for the regulation of ionotropic glutamatergic signaling at the postsynaptic membrane, plays an unanticipated and essential role in mediating the actions of hallucinogens and atypical antipsychotic drugs at 5-HT 2A and 5-HT 2C serotonergic G-protein-coupled receptors. We show that PSD-95 is crucial for normal 5-HT 2A and 5-HT 2C expression in vivo and that PSD-95 maintains normal receptor expression by promoting apical dendritic targeting and stabilizing receptor turnover in vivo . Significantly, 5-HT 2A - and 5-HT 2C -mediated downstream signaling is impaired in PSD-95 null mice, and the 5-HT 2A -mediated head-twitch response is abnormal. Furthermore, the ability of 5-HT 2A inverse agonists to normalize behavioral changes induced by glutamate receptor antagonists is abolished in the absence of PSD-95 in vivo . These results demonstrate that PSD-95, in addition to the well known role it plays in scaffolding macromolecular glutamatergic signaling complexes, profoundly modulates metabotropic 5-HT 2A and 5-HT 2C receptor function.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 29
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
- Rapid modulation of spine morphology by the 5-HT 2A serotonin receptor through kalirin-7 signaling Proceedings of the National Academy of Sciences November 4, 2009
- Htr2a gene and 5-HT2A receptor expression in the cerebral cortex studied using genetically modified mice Frontiers in Neuroscience 2010
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
- Serotonin, But Not N -Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo Journal of Neuroscience October 6, 2010
and 24 more in the library
Cites 11
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- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex Journal of Neuroscience October 1, 2003
- A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain Neuropsychopharmacology May 1, 2002
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and 6 more in the library