Serotonin and brain function: a tale of two receptors

By Robin L. Carhart-Harris, David J. Nutt. Journal of Psychopharmacology, 2017

647 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Clinical Psychology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/11f877df3f2f2eb4fc3a44e57741722b1b469aae

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Robin L. Carhart-Harris
2. Karl J. Friston
3. David J. Nutt
4. Leor Roseman

In Clinical Psychology

1. Robin L. Carhart-Harris
2. David J. Nutt
3. Karl J. Friston
4. Leor Roseman
5. R. Watts
6. Camilla M. Day
7. S. Pilling

In Organic Chemistry

1. Robin L. Carhart-Harris
2. Karl J. Friston
3. David J. Nutt
4. Leor Roseman
5. R. Watts

Citations in the corpus

• Psilocybin with psychological support for treatment-resistant depression: six-month follow-up (2017, background): “This paradox implies that 5-HT2AR agonism and antagonism can achieve consistent ends, in terms of alleviating depressive symptoms, but via different mechanisms (see Carhart-Harris et al. (2017) and Carhart-Harris and Nutt (2017) for a relevant discussion).”
• REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics (2019, background): “We argue that this upregulation of 5-HT2AR functioning facilitates adaptability to environmental volatility (Carhart-Harris and Nutt, 2017).”
• Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression (2018, background): “These findings may imply that enhanced sensitivity to context is an important function of 5-HT2A receptor signaling (Carhart-Harris and Nutt, 2017).”
• Review on Fundamental of Electroencephalography and Detection Techniques in Substance and Behavioral Addiction (2025, unknown): “This includes projections to the nucleus accumbens reward center (35).”