Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases
Dasiel O Borroto-Escuela, Patrizia Ambrogini, Manuel Narváez, Valentina Di Liberto, Sarah Beggiato, Luca Ferraro, Ramón Fores‐pons, Jose Erik Alvarez‐contino, Alexander López‐salas, Giuseppa Mudò, Zaida Dı́az-cabiale, Kjell Fuxé
Cells July 27, 2021 DOI: 10.3390/cells10081902 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Relevance law Cognitive science |
| Citations | 29 |
| Key points | Proposes that heteroreceptor complexes and their allosteric receptor-receptor interactions constitute a novel biological principle for signal integration and targets for CNS disease treatment, including explaining mechanisms of atypical antipsychotics, hallucinogens, and antidepressants. |
Abstract
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.
Comparable studies
Other theoretical and historical papers on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics as Medicines: An Emerging New Paradigm General population | 2016 | Theoretical or philosophical paper | |
| Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate | 2018 | Theoretical or philosophical paper | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Dreams, Hallucinogenic Drug States, and Schizophrenia: A Psychological and Biological Comparison | 1983 | Theoretical or philosophical paper | |
| Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cited by 9
- Mini-review: The neurobiology of treating substance use disorders with classical psychedelics Frontiers in Neuroscience April 17, 2023
- The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics. Neurochemical Research April 1, 2023
- Trauma and Remembering: From Neuronal Circuits to Molecules Life October 26, 2022
- Applications and Potential of In Silico Approaches for Psychedelic Chemistry Molecules August 9, 2023
- Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies Biological Psychiatry February 1, 2026
and 4 more in the library
Cites 10
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology July 19, 2010
- Evidence for a central 5‐hydroxytryptamine receptor stimulation by lysergic acid diethylamide British Journal of Pharmacology September 1, 1968
- Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology December 17, 2013
and 5 more in the library