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Serotonin and brain function: a tale of two receptors.

R L Carhart-Harris, D J Nutt

Journal of Psychopharmacology August 31, 2017 DOI: 10.1177/0269881117725915 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Theoretical or philosophical paper Peer reviewed
Topics Depression Serotonin
Keywords Brain Animals Humans Receptor, serotonin, 5-ht1a Receptor, serotonin, 5-ht2a Hallucinogens Antidepressive agents Synaptic transmission Psychedelics
Key points Argues that serotonin neurotransmission supports two adaptive responses to adversity: passive coping mediated by postsynaptic 5-HT1A receptor signalling and characterised by stress moderation, and active coping mediated by 5-HT2A receptor signalling and characterised by enhanced plasticity. Proposes that SSRIs enhance the 5-HT1A pathway while 5-HT2A-agonist psychedelics enhance the 5-HT2A pathway, explaining complementary therapeutic outcomes.

Abstract

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

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

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