In most vertebrates' brains, serotoninergic neurons are located in the Raphe nuclei.
The serotonergic neurons located in Raphe nuclei are affected by many areas of the brain, mainly including glutamatergic fibers and GABA fibers from ventromedial prefrontal cortex and cingulate cortex, GABA fibers from Preoptic area and Rostral ventromedial medulla.
And different types of serotonin receptors are widely located on different types of neurons in the brain.
Among the more important ones are: 5-HT1A receptor, 5-HT2A receptor and 5-HT2C receptor.
The 5-HT1A receptor is mainly located on the serotonergic neurons themselves, the glutamate neurons in the frontal/parietal cortex and the hippocampus, dopaminergic/noradrenergic/acetylcholineergic neurons in the striatum and Midbrain.
When activated, it inhibits the release of serotonin itself, inhibits glutamatergic pyramidal neurons, and increases the release of dopamine/norepinephrine/acetylcholine.
The 5-HT2A receptor is mainly located on the glutamate neurons in the frontal/parietal cortex and the hippocampus, dopaminergic neurons in the midbrain, endocrine cells in anterior pituitary.
When activated, it increases the glutamatergic neurons in the frontal/parietal cortex, inhibits the release of dopamine, and increases the release of GH/ICSH/ACTH/PRL/etc.
The 5-HT2C receptor is mainly located on the dopaminergic neurons and noradrenergic neurons in the striatum and hypothalamus.
When activated, it inhibits the release of dopamine and norepinephrine.
The above-mentioned three types of 5-HT receptors play an important role in mood regulation[1] .
The specific regulation is complex and each receptor has two sides.
Inhibition of dopamine and norepinephrine can reduce cortical activity and lead to symptoms of depression. The 5-HT2C receptor inhibits the release of dopamine to the nucleus accumbens and increases anxiety symptoms.
Inhibition of glutamatergic activity in the cortex also leads to symptoms of depression.
Increases the release of ACTH can protect cognitive function by reducing the release of CRH. Because CRH can lead to the aggregates of Tau protein and the axonal transport disorders in hippocampal neurons[2].
(This picture is from Reference[1] )
In addition, 5-HT3 receptor and 5-HT7 receptor also play important role.
5-HT3 receptor is widely located on the central nervous system and digestive system, mediate fast excitatory synaptic transmission and regulate vomiting.
The distribution of the 5-HT7 receptor is more extensive, it is involved in thermoregulation, circadian rhythm, memory, sleep, and plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract.
In addition, 5-HT3 receptor and 5-HT7 receptor in the spinal dorsal horn play an opposite role in the activation and inhibition of nociceptive neurons[3][4]. The 5-HT3 receptors activate nociceptive neurons and the 5-HT7 receptors inhibit nociceptive neurons.
5-HT4, 5-HT5 and 5-HT6 in the regulation of the nervous system are also important.
Here we can see the particularity of the serotonin receptor system.
In most cases, the two mutual antagonisms are mediated by different neurotransmitters. For example, acetylcholineergic sympathetic and noradrenergic parasympathetic nerves antagonize each other.
However, many antagonisms are mediated by serotonin, just involve different types of serotonin receptors, this is very rare in other neurotransmitters.
Comparing the genes of different neurotransmitter receptors, the study found that the ‘primordial’ serotonin receptor evolved over 750 million years ago[5]. Most Serotonin receptors, except the 5-HT3 receptor , started to differentiate at that time. This date likely to predate the evolution of muscarinic, dopaminergic and adrenergic receptor systems.
It may be based on the physicochemical properties of serotonin make it is easy to be obtained and synthesized by cells, or it may also be completely accidental. The nervous system first selects 5-HT receptors to undertake complex regulatory functions and forms the 5-HT receptors system of today.
References
[1] Ll V D H. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications (4th edition)[J]. Journal of Child & Adolescent Mental Health, 2014, 26(2):157-158.
[2] Zhang L F, Shi L, Liu H, et al. Increased hippocampal tau phosphorylation and axonal mitochondrial transport in a mouse model of chronic stress[J]. International Journal of Neuropsychopharmacology, 2012, 15(3): 337-348.
[3] Dogrul A, Ossipov M H, Porreca F. Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors[J]. Brain research, 2009, 1280: 52-59.
[5] Peroutka S J. Serotonin receptor subtypes[J]. Cns Drugs, 1995, 4(1): 18-28.