Figure 3.

Central pathways mediating fatigue. The key neurotransmitters are serotonin [5HT], dopamine [DA], corticotropin release hormone [CRH], norepinephrine, and endocannabinoids. The most important amongst these [5HT, DA, and CRH] are color coded. The neurotransmitters may be produced locally in the brain or gut derived [e.g., 5HT]. The same neurotransmitter may have a contrasting effect depending on its projections. The receptor subtypes [not shown here] of these neurotransmitters are also clinically relevant. For example, SSRIs [selective serotonin receptor uptake inhibitors] act on 5HT1A receptors, and ondansetron acts on 5HT3 receptors, yet both have been used clinically to treat fatigue and depression. The important projection pathways are DA: Substantia nigra [SN] and ventral tegmental area [VTA] projecting to the striatum, basal ganglia, and frontal cortex. 5HT: Raphe nucleus [brainstem] projecting to the striatum, basal ganglia, and frontal cortex. CRH: hypothalamus, bed nucleus of stria terminalis [BNST], and frontal cortex projecting to the striatum and basal ganglia and regulating DA transmission. CRH pathways are important in states of inflammation. The hypothalamus-pituitary-adrenal [HPA] axis has an important role to play in this situation. High cortisol inhibits CRH release, leading to diminished motivation and fatigue.