6.1.1. Serotonin

Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter produced mainly in the gastrointestinal tract and also by the raphe nuclei, located in the brainstem. Thus, 5-HT has multifaceted functions and modulates food intake, body weight control, mood, cognition, learning and memory. There are many 5-HT receptors, ranging from 5-HT1 to 5-HT7, with a high density of receptors in the prefrontal cortex and hippocampus [94]. However, the 5-HT1 and 5-HT2 receptor families are of the most interest in the context of AN.

There is evidence for dysfunctions in the serotonin system in AN. For example, patients with AN show reduced levels of serotonin and markers of serotonin (e.g., tryptophan) in the acute stages, which normalise after recovery [95], together with depletions in 5-HT1A and 5-HT2A receptor densities [96]. However, some abnormalities persist after recovery. For example, 5-HT2A receptor activity has been found to be abnormal in individuals recovered from AN [97]. Additionally, there have been several studies indicating genetic differences related to serotoninergic activity in AN (e.g., the S allele of the 5-HTTLPR gene [98,99]), one of which is a polymorphism of the 5-HT2A receptor gene [100,101].

It is possible that the dietary restriction associated with AN leads to a depletion of the dietary supplies of tryptophan, which is an amino acid that is a chemical precursor to 5-HT. Alterations in serotonin signalling in limbic pathways (e.g., mesocorticolimbic pathway) and structures (e.g., the hippocampus, hypothalamus, amygdala and thalamus) may contribute to various features of AN, such as obsessiveness, body image distortions, low mood, anxiety, fear, dietary behaviour and their response to SSRIs [102].

Several studies have suggested that the antidepressant effects of ketamine are partially due to its effects on 5-HT, showing some similarities to traditional SSRIs. In vivo microdialysis studies in rodents given an acute subanaesthetic dosage of ketamine showed increases in 5-HText in the mPFC [103]. Additionally, a study in nonhuman primates demonstrated a downregulation of selective 5-HT transporters (SERT) after an acute IV ketamine injection [104]. Overall, there is evidence for the importance of 5-HT1A and 5-HT1B receptor agonism for the antidepressant effects of ketamine (see [105] for a review). It is thought that this may occur as a downstream effect of hippocampal NMDA receptor inhibition and AMPA receptor activation. This may normalise the aforementioned alterations shown in AN and improve mood and/or comorbid depression.
