The Hallucinogenic Serotonin2A Receptor Agonist, 2,5-Dimethoxy-4-Iodoamphetamine, Promotes cAMP Response Element Binding Protein-Dependent Gene Expression of Specific Plasticity-Associated Genes in the Rodent Neocortex
Lynette A. Desouza, Madhurima Benekareddy, Sashaina E. Fanibunda, Farhan Mohammad, Balaganesh Janakiraman, Utkarsha Ghai, Tamar Gur, Julie A. Blendy, Vidita A Vaidya
Frontiers in Molecular Neuroscience December 24, 2021 DOI: 10.3389/fnmol.2021.790213 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat cortical neurons and rodent neocortex |
| Interventions | 2 5-dimethoxy-4-iodoamphetamine (DOI) |
| Topics | Neuroplasticity Serotonin |
| Keywords | Creb Immediate early gene Cell biology Neocortex Arc geometry Downregulation and upregulation Transcription factor Receptor Gene expression Genetics |
| Citations | 46 |
| Key findings | DOI upregulates neuronal plasticity-associated genes through CREB-dependent and -independent pathways, with CREB required for full induction of Arc, cFos, and Cebpb. |
Abstract
Psychedelic compounds that target the 5-HT 2A receptor are reported to evoke psychoplastogenic effects, including enhanced dendritic arborization and synaptogenesis. Transcriptional regulation of neuronal plasticity-associated genes is implicated in the cytoarchitectural effects of serotonergic psychedelics, however, the transcription factors that drive this regulation are poorly elucidated. Here, we addressed the contribution of the transcription factor cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) in the regulation of neuronal plasticity-associated genes by the hallucinogenic 5-HT 2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). In vitro studies with rat cortical neurons indicated that DOI enhances the phosphorylation of CREB (pCREB) through mitogen-activated protein (MAP) kinase and calcium/calmodulin dependent kinase II (CaMKII) pathways, with both cascades contributing to the DOI-evoked upregulation of Arc, Bdnf1, Cebpb , and Egr2 expression, whilst the upregulation of Egr1 and cFos mRNA involved the MAP kinase and CaMKII pathway respectively. We observed a robust DOI-evoked increase in the expression of several neuronal plasticity-associated genes in the rat neocortex in vivo . This DOI-evoked upregulation of neuronal plasticity-associated genes was completely blocked by the 5-HT 2A receptor antagonist MDL100,907 in vitro and was also abrogated in the neocortex of 5-HT 2A receptor deficient mice. Further, 5-HT 2A receptor stimulation enhanced pCREB enrichment at putative cAMP response element (CRE) binding sites in the Arc , Bdnf1 , Cebpb , cFos , but not Egr1 and Egr2 , promoters in the rodent neocortex. The DOI-mediated transcriptional induction of Arc , cFos and Cebpb was significantly attenuated in the neocortex of CREB deficient/knockout (CREBαδ KO) mice. Collectively, these results indicate that the hallucinogenic 5-HT 2A receptor agonist DOI leads to a rapid transcriptional upregulation of several neuronal plasticity-associated genes, with a subset of them exhibiting a CREB-dependent regulation. Our findings raise the intriguing possibility that similar to slow-acting classical antidepressants, rapid-action serotonergic psychedelics that target the 5-HT 2A receptor may also recruit the transcription factor CREB to enhance the expression of neuronal plasticity-associated genes in the neocortex, which could in turn contribute to the rapid psychoplastogenic changes evoked by these compounds.
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 35
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity. Biochemistry January 21, 2022
- 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines. ACS Chemical Neuroscience February 1, 2023
- Canalization and plasticity in psychopathology Neuropharmacology December 27, 2022
- Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player? Neuropsychopharmacology March 1, 2024
and 30 more in the library
Cites 27
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Journal of Neuroscience April 15, 1997
and 22 more in the library