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Serotonin

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Serotonin

Serotonin is an important neurotransmitter in the central nervous system (CNS). It also has peripheral significance (in the body). This illustration refers to serotonin in the brain.

Most serotonin-producing neurons are located in the raphe nuclei in the midbrain.
Raphe nuclei project serotonergically in a highly branched manner throughout the brain1 in a tonic rhythm of 1 to 5 peaks/second. The frequency of serotonin release is increased by norepinephrine at adrenoceptors and decreased by serotonin at somatodendritic 5-HT-1A autoreceptors.2 Somatodendritic and presynaptic serotonin autoreceptors are part of a negative feedback loop that serves to limit excessive serotonin production.3 This negative feedback loop is impaired in some disorders.

Serotonin is involved in many neurophysiological mechanisms and has a broad regulatory range. Serotonin is required for the stress responses of the HPA axis.
Tonic serotonergic activity is highest during periods of awakening arousals, whereas it is reduced during quiet wakefulness and slow-wave sleep and is absent altogether during REM sleep.4

Serotonin is significant in prenatal brain development. In the early development of the CNS, serotonin influences 5

  • Cell proliferation
  • Cell migration
  • Cell differentiation

Serotonin increases prolactin and ACTH levels.6

Serotonin deficiency in the basolateral amygdala causes a reduction in long-term potentiation by increased glutamate and decreased GABA levels in adult female mice exposed to chronic 4-vinylcycloxendiepoxide, which induces anxiety symptoms.7

Serotonin is degraded to 5-HIAA.

1. Serotonin neurons, receptors, transporters

1.1. Serotonin receptors

The following illustration of serotonin receptors is based on Jørgensen.8
So far, 7 main groups of serotonin receptors are known, 5-HT-1 to 5-HT-7. These in turn subdivide into subgroups, e.g. 5-HT2a, 5-HT-2b, 5-TH-2c.

1.1.1. 5-HT1A

  • In the dorsal raphe nuclei and the limbic system
  • Pre- and postsynaptic9
  • Inhibits adenylate cyclase (AC)
    • Inhibition of AC causes memory and learning defects.10
    • Inhibition of AC by binding to the Opiate receptor
    • Inhibition of AC contributes to the development of addiction10
    • Toxins such as cholera toxin and pertussis toxin act by permanent activation of adenylate cyclase.10
  • Autoreceptor
    • Regulates the inhibition of serotonin production by raphe nuclei11
  • Regulates
    • Mood
    • Fear
    • Temperature
    • Feeding
    • Movement
  • Predominantly inhibitory11
  • Agonists
    • 5-CT
    • 8-OH-DPAT
    • RU 24969
  • Antagonists
    • WAY-100635
    • Cyanopindolol
    • Metysergide
  • Stress
    • Acute stress increased gene expression of the 5-HT7 receptor in the CA1 region of the hippocampus.12 while gene expression of the 5-HT1A receptor decreased13
    • Corticosterone dose-dependently affects 5-HT1A receptor-mediated responses in rat hippocampus in vitro and in vivo: activation of only the high-affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated responses, whereas additional activation of lower affinity glucocorticoid receptors enhances 5-HT effects.14
    • Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animals.14
  • Functional variations in the 5-HT1A gene (HTR1A) appear to be related to15
    • Personality traits of negative emotionality
    • The development of anxiety disorders
  • 5-HT1A activation decreases NMDA receptor-mediated currents in pyramidal neurons of the PFC.15

1.1.2. 5-HT1B

  • In substantia nigra, basal ganglia, frontal cortex
  • Regulates
    • Neurotransmitter release
      • Activation of 5-HT1B inhibits transmitter release.
        This significantly reduces excitatory transmission in the thalamocortical regions of the visual and somatosensory systems.
        5-HT1B receptors thus appear to regulate thalamic cortex development by inhibiting glutamate release.15
      • 5-HT filters glutamatergic input from cortex and thalamus into the basolateral amygdala through activation of presynaptic 5-HT1B receptors, not 5-HT1A receptors.16
    • Vascular functions
  • Predominantly inhibitory17
  • Agonists
    • 5-CT
    • RU 24969
  • Antagonists
    • Cyanopindolol

1.1.3. 5-HT2A

  • In the cortex, hippocampus, caudate nucleus
  • Stimulates phospholipase
  • Regulates
    • Sleep
    • Motor functions
    • Behavior
  • Predominantly facilitating other processes of action17
  • Agonists
    • DOI
    • MCPP
    • S-α-methyl-serotonin / Sα-methyl-5-HT
  • Antagonists
    • Metergoline
    • Metysergide
    • Flourobenzoyl
    • Ketanserin
      • Administration of the 5HT2 receptor antagonist ketanserin to the amygdala inhibits ACTH synthesis on light stress18
        • This suggests that serotonin activates the HPA axis also via limbic structures19
    • LY 53857
    • Quetiapine, Seroquel (antipsychotic)
  • Serotonin causes an inhibition of dopamine release at 5-HT2A. 5-HT2A antagonists prevent this.
  • Serotonin supports the exitatory effects of glutamate in the nucleus motorius nervi facialis, which controls motor processes and facial expressions. This support is prevented by 5-HT2 antagonists.20
  • 5-HT2A as well as 5-HT2C receptors appear to downregulate readily upon chronic activation, but are not subject to upregulation upon chronic underactivation. Moreover, chronic treatment with serotonin antagonists leads to a paradoxical downregulation of 5-HT2A and 5-HT2C receptors.11
  • 5-HT2A activation increases NMDA receptor-mediated currents in pyramidal neurons of the PFC.15

1.1.4. 5-HT2B

  • Predominantly facilitating other processes of action17
  • Agonists
    • S-α-methyl-serotonin / Sα-methyl-5-HT

1.1.5. 5-HT2C

  • In hypothalamus, limbic system, basal ganglia
  • Regulates
    • Synaptic plasticity (significant)15
    • Penis erection
  • Predominantly facilitating other processes of action17
  • Agonists
    • DOI
    • MCPP
    • MK 21
    • S-α-methyl-serotonin / Sα-methyl-5-HT
  • Antagonists
    • Metergoline
    • Metysergide
    • Ketanserin
      • Administration of the 5HT2 receptor antagonist ketanserin to the amygdala inhibits ACTH synthesis on light stress18
        • This suggests that serotonin activates the HPA axis also via limbic structures19
    • LY 53857
    • SB 242084
    • Quetiapine / Seroquel (antipsychotic)
  • 5-HT2A as well as 5-HT2C receptors appear to downregulate readily upon chronic activation, but are not subject to upregulation upon chronic underactivation. Moreover, chronic treatment with serotonin antagonists leads to paradoxical downregulation of 5-HT2A and 5-HT2C receptors.11
  • 5-HT2C activation increases NMDA receptor-mediated currents in pyramidal neurons of the PFC.15

1.1.6. 5-HT3

  • In pons, brainstem,8 entorhinal cortex, area postrema11
  • Regulates
    • Vomiting reflex
    • Gastrointestinal movements (e.g. bowel movements)
    • Cardiovascular system
    • Pain perception21
    • Reward system21
    • Cognition21
    • Depression21
    • Anxiety Control21
  • Fast excitatory action17
  • Agonists
    • SR 57227
    • M-CPBG
    • Y-25130
    • Ondansetrone
    • ICS 205-930
  • Stimulation of 5-HT3 receptors in the striatum increases endogenous dopamine output.2
  • 5-HT3R antagonists21
    • Inhibit the binding of serotonin to postsynaptic 5-HT3 receptor
    • Increase the availability of serotonin for other receptors such as 5-HT1A, 1B and 1D as well as 5-HT2
    • Have an antidepressant effect
    • Play an important role in mood and stress disorders

1.1.7. 5-HT4

  • In cortex, hypothalamus
  • Regulates
    • Memory
    • Neurotransmitter release
  • Facilitates other knitting processes17
  • Agonist
    • RS 67506
  • Antagonists
    • ICS 205-930
    • RS 2359

1.1.8. 5-HT5A

  • In cortex, hippocampus, hypothalamus
  • Regulates
    • Sleep
    • Motor functions
    • Behavior
  • Agonists
    • 5-CT

1.1.9. 5-HT5B

  • In the dorsal raphe nuclei, in CA 1 region of the hippocampus, olfactory bulb
  • Regulates
    • Unknown

1.1.10. 5-HT6

  • In striatum, hippocampus, cortex
  • Regulates
    • Cholinergic system
    • Feeding
  • Antagonists
    • Metergoline

1.1.11. 5-HT7

  • In Limbic system, nucleus suprachiasmaticus, dorsal raphe nuclei
  • Regulates
    • Mood
    • Fear
    • Temperature
    • Sleep cycles
  • Facilitates other knitting processes17
  • Agonists
    • 5-CT
    • 8-OH-DPAT
  • Antagonists
    • Metergoline
    • Metysergide
  • Stress
    • Acute stress increased 5-HT7 receptor gene expression in the CA1 region of the hippocampus,12 while 5-HT1A receptor gene expression decreased13

1.2. Effect of antidepressant drugs and treatment on receptors

The following presentation is based on Cooper et al.22

1.2.1. Somatodendritic 5-HT-1A autoreceptor

  • SSRI: long-term use reduces receptor sensitivity
  • MAO-A reuptake inhibitors: long-term use reduces receptor sensitivity
  • 5-HT-1A agonists: long-term use reduces receptor sensitivity
  • Tricyclic antidepressants: no effect
  • Electroconvulsive therapy: no effect

The effects of SSRIs, MAO-A reuptake inhibitors, and 5-HT-1A agonists could be understood as a reduction in upregulation of the receptor to serotonin deficiency.

1.2.2. Presynaptic 5-HT autoreceptors

  • SSRI: long-term use reduces receptor sensitivity
  • MAO-A reuptake inhibitors: no effect
  • 5-HT-1A agonists: no effect
  • Tricyclic antidepressants: no effect
  • Electroconvulsive therapy: no effect

1.2.3. Preynaptic alpha-2 adrenoceptors

  • SSRI: no effect
  • MAO-A reuptake inhibitors: long-term use reduces receptor sensitivity
  • Electroconvulsive therapy: no effect

1.2.4. Postsynaptic 5-HT receptors

  • SSRI: no effect
  • MAO-A reuptake inhibitors: no effect or reduced receptor sensitivity by long-term use
  • 5-HT-1A agonists: no effect
  • Tricyclic antidepressants: long-term use increases receptor sensitivity
  • Electroconvulsive therapy: long-term treatment increases receptor sensitivity

1.2.5. Serotonin level change

  • SSRI: Increase
  • MAO-A reuptake inhibitors: increase
  • 5-HT-1A agonists: increase
  • Tricyclic antidepressants: increase
  • Electroconvulsive therapy: increase

1.3. Serotonin transporter

Psychosocial stress resulted in significantly lower gray matter volume in the precentral gyrus, middle and superior frontal gyri, frontal pole, and cingulate gyrus in carriers of the S allele of the serotonin transporter than in carriers of the L allele. Gray matter volume in the frontal pole and anterior cingulate gyrus mediated the association of this gene-environment interaction with the number of ADHD symptoms.23

The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with increased ADHD risk. In carriers of this haplotype, stress exposure and ADHD severity correlate more strongly than in non-carriers. This gene-environment interaction is again enhanced if they were also carriers of the homozygous 5-HTTLPR L allele, rather than the S allele. These bilateral and trilateral interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex, and angular gyrus. This provides evidence that gene variants in the HPA axis stress response pathway influence how stress exposure affects ADHD severity and brain structure.24

2. Regulatory ranges of serotonin

  • Impulse Control25265
  • Situational recall of behaviors, especially in response to emotions27
    • Together with dopamine
  • Controlling the intensity of the stress response27
    • Together with dopamine
    • 5-HT particularly strongly innervates forebrain stress integrative structures, including28
      • Hippocampus
      • PFC
      • Amygdala
      • Hypothalamus
    • Deactivation (lesion) of raphe nuclei (electrolytically or neurochemically by DHT) decreases HPA axis responses to stress by19
      • Movement restriction (serotonin reduction decreases ACTH secretion by 50%)29
        • In contrast, no reduction in ACTH secretion by 5-HT antagonists on swimming stress, ether treatment, or endotoxin.
      • Ether30; different on the other hand 29
      • Administration of the 5-HT antagonist DHT into the PVN in relation to ether stress30
      • Glutamate administration in the PVN31
        • Suggesting that serotonin acts directly on the PVN, mediating stress responses there
        • As well as norepinephrine (via α1-adrenoceptors), by the way32
      • Stimulation of the dorsal hippocampus30
      • Stimulation of the central amygdala30
        • Where serotonin mediates this stress inhibitory effect in the PVN via 5-HT-2 receptors32
    • Administration of a 5HT2 receptor antagonist to the amygdala inhibits ACTH synthesis on light stress18
      • This suggests that serotonin activates the HPA axis also via limbic structures19
  • Emotions/emotional control3334
    • Affect Control27
      • Together with dopamine
    • Mood33
    • Aggression2526535
    • Anxiety2526528
    • Drive33
    • Mental well-being33
    • Emotion memory in the amygdala and limbic system33
  • Stimulus intensity control36
  • Low serotonin levels cause emotional deficits in ADHD37
  • Pain perception2534
  • Sleep-wake rhythm3834
  • Eating behavior2534
  • Sexual behavior3934
  • Antisocial personality disorder40

3. Symptoms of serotonin deficiency

Serotonin deficiency in the brain:

  • Lack of drive33
  • Sadness33
  • Fears3341
  • Constraints3337
  • Depressive moods / depression3337441
  • Aggression26535441
  • Stomach/intestinal complaints33
    • Serotonin, as a messenger substance, also regulates the nervous system of the digestive tract33
    • Eating disorders / satiety41
  • Emotional deficits37
  • Inadequate executive functions37
  • Learning Difficulties37
    • Memory impairment41
  • Impulse inhibition problems (when dopamine is involved at the same time)42
  • Sleep disorders41

Peripheral (somatic) symptoms of serotonin deficiency:41

  • Vasoconstriction (coronary spasm)
  • Irritable colon (irritable bowel syndrome)
  • Fibromyalgia (pain sensitivity)
  • Scoliosis
  • Thrombosis tendency (platelet aggregation)
  • Inflammation (immune dysfunction)
  • Melatonin deficiency

Serotonin deficiency in the brain and body:41

  • Headache
  • Migraine

Serotonin is also involved in schizophrenia.4

Taking methylphenidate is thought to have effects on serotonin levels.37

It is striking that serotonin deficiency is associated on the one hand with internalizing disorders (depression, anxiety) and at the same time with externalizing disorders (aggression, impulse control, antisocial personality disorder).

4. Serotonin formation

Serotonin formation is increased by

  • Zen Meditation
    Meditation can increase brain serotonin levels over the long term, so not just during meditation itself.42
  • Vitamin D3.43 D3 increases (especially in winter) also in healthy people the mood44 by increasing the synthesis of serotonin.45
    In Germany, 60% of all people suffer from D3 deficiency.
    Especially during the months of October to April, the natural sunlight intensity is not sufficient to produce enough D3. For more on this topic, see Vitamin D3 In the article Vitamins and minerals in ADHD in the section Medications for ADHD - Overview of the chapter ADHD - Treatment and therapy.
    ADHD sufferers have a higher than average incidence of D3 deficiency.
  • Acetyl-L-carnitine (0.5 g/kg for 25 days) increased serotonin levels in the cortex and norepinephrine levels in the hippocampus in mice.46 GABA, glutamate and glutamine remained unchanged.

Serotonin formation is reduced by

  • Stress33

5. Serotonin and ADHD

Serotonin is more secondarily involved in ADHD and is thought to be more relevant in ADHD-I (without hyperactivity).47

We wonder, however, whether serotonin deficiency might contribute to the HPA responses often flattened in ADHD-HI. It is open how this can be reconciled with the HPA axis responses that are often exaggerated in ADHD-I.

One study of children with ADHD found that increased methylation of the serotonin transporter gene promoter correlated with increased hyperactivity and impulsivity and increased impulsive errors in a sustained attention task.48 In contrast, another study found that lower methylation of the serotonin transporter gene (and the DRD4 gene) in newborns correlated with increased ADHD symptoms at age 6.49

Empirically, serotonergic drugs are known to have an effect on impulsivity.

The dopamine transporters (DAT), which are primarily located in the striatum and are overactivated in ADHD, also have a serotonergic affinity in the striatum, i.e., they also reuptake serotonin,50 at least when serotonin transporter activity is impaired.51

Serotonin elevation directly induced in the striatum simultaneously increased dopamine concentration in the striatum.52

6. Other mental disorders due to dysfunction of the serotonergic system

  • Depression5354
  • Anxiety disorders154
  • Schizophrenia154
  • Addictive disorders154
  • Infantile autism5556557
  • Eating disorders54
  • Vomiting54
  • Obsessive Compulsive Disorder5954
  • Cancer54
  • Circadian rhythm disturbances54
  • Developmental Disabilities54
  • Migraine54
  • Neurodegenerative disorders54
  • Muscle twitching (myoclonus)54
  • Pain sensitivity54
  • Premenstrual syndrome54
  • Post-traumatic stress disorder54
  • Sexual disorders54
  • Sleep disorders54
  • Stress disorders54
    • Activation of serotonin 5-HT-1A receptors in the dorsomedial hypothalamus inhibits stress-induced activation of the HPA axis in rats.60

ADHD is primarily dopaminergic, secondarily noradrenergic. There is a further, albeit smaller, connection to the serotonergic system.

7. Treatment with serotonergic drugs (disorders)

  • Depression59
  • Obsessive Compulsive Disorder59
  • Anxiety and panic disorders59

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