Serotonin and brain function: a tale of two receptors

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.

Keywords: Depression; psychedelics; serotonin.

Figure 1.

Regional distribution of serotonin 1A (left) and 2A receptors (right) in healthy volunteers as measured using PET imaging and radioligands selective for the 5-HT 1A and 2A receptors. Pathway 1 refers to the ‘passive coping’ pathway hypothesised to be mediated by 5-HT1AR signalling and concerned with passive endurance, and ‘pathway 2’ refers to the ‘active coping’ pathway hypothesised to be mediated by 5-HT2AR signalling and concerned with an active change in outlook and/or behaviour. Images reproduced from (Beliveau et al., 2016) with permission. Note: The dense expression of the 5-HT1AR in medial temporal lobe regions and particularly the hippocampus is not clearly evident in the relevant maps shown here (left) but can be seen in values presented in the paper itself, as well as others (Pazos and Palacios, 1985; Pazos et al., 1987).

Figure 2.

Extra-pharmacological (EP) model of drug action. This model is intended to provide a comprehensive account of the action of psychoactive drugs that takes into account important extra-pharmacological components such as trait, pre-state, dosage and environmental factors and how these interact with a given drug’s specific pharmacology to predict the quality of the acute ‘intoxicated’ or ‘medicated’ state and subsequent longer-term outcomes. The model is conceived with acute dosing in mind; however, it could also be adapted and applied to chronic dosing regimens.

Figure 3.

A two-part or ‘bipartite’ model of brain serotonin function. Model proposes that brain serotonin mediates adaptive responses to adversity via two distinct mechanisms: one mediated by postsynaptic 5-HT1AR signalling in aid of stress moderation (pathway 1) and the other mediated by 5-HT2AR signalling is aid of more substantial adaptive changes (pathway 2). SSRIs and other conventional antidepressant medications work on and can enhance pathway 1, whereas pathway 2 can be enhanced by 5-HT2AR agonist psychedelic drugs such as psilocybin. Note: it is hypothesised that active coping can be most effectively implemented if the window of plasticity afforded by 5-HT2AR agonism is complemented by supportive psychotherapy that promotes a willingness to confront and work through sources of stress (Watts et al., 2017). Illustrations by Samantha Strong (S.L.Strong1@bradford.ac.uk).