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.
Serotonin is involved in many neurophysiological mechanisms and has a broad regulatory range. Serotonin is required for the stress reactions of the HPA axis.
Tonic serotonergic activity is highest during periods of awakening arousal, while it is reduced during quiet wakefulness and slow-wave sleep and completely absent during REM sleep.¹

• 1. Formation of serotonin
• 2. Control ranges of serotonin
• 3. Symptoms of serotonin deficiency
• 4. Serotonin neurons, receptors, transporters
  • 4.1. Serotonin receptors
    • 4.1.1. 5-HT1A
    • 4.1.2. 5-HT1B
    • 4.1.3. 5-HT2A
    • 4.1.4. 5-HT2B
    • 4.1.5. 5-HT2C
    • 4.1.6. 5-HT3
    • 4.1.7. 5-HT4
    • 4.1.8. 5-HT5A
    • 4.1.9. 5-HT5B
    • 4.1.10. 5-HT6
    • 4.1.11. 5-HT7
  • 4.2. Effect of antidepressant medication and treatment on receptors
    • 4.2.1. Somatodendritic 5-HT-1A autoreceptor
    • 4.2.2. Presynaptic 5-HT autoreceptors
    • 4.2.3. Preynaptic alpha-2 adrenoceptors
    • 4.2.4. Postsynaptic 5-HT receptors
    • 4.2.5. Change in serotonin levels
• 5. Reuptake and breakdown of serotonin
  • 5.1. Serotonin transporter
  • 5.2. Serotonin degradation
• 6. Serotonin and ADHD
• 7. Other mental disorders due to malfunctions of the serotonergic system
• 8. Treatment with serotonergic medication (disorders)

1. Formation of serotonin¶

Peripherally (in the body), serotonin is primarily synthesized in the enterochromaffin cells of the intestinal mucosa.
It is transported in the blood by thrombocytes and basophilic granulocytes and can therefore exert its effect in almost every body tissue²
Serotonin is mainly produced in the cell bodies of neurons of the raphe nuclei.³⁴

• Dorsal raphe nucleus (DRN)
  • 50 % of DRN cells synthesize serotonin
• Medial raphe nucleus (MRN)
  • 5 % of DRN cells synthesize serotonin

DRN and MRN project to numerous cortical and subcortical brain regions, in particular:⁵

• Amygdala
• Hypothalamus
• Thalamus
• Superior colliculus
• mPFC
• sensorimotor cortex
• Putamen
• Caudate nucleus
• Septum

Tonic serotonin injection occurs in a rhythm of 1 to 5 peaks/second. The frequency of serotonin release is increased by noradrenaline at adrenoceptors and decreased by serotonin at the somatodendritic 5-HT-1A autoreceptors.⁶ Somatodendritic and presynaptic serotonin autoreceptors are part of a negative feedback loop that serves to limit excessive serotonin production.⁷ This negative feedback loop is impaired in some disorders.
Serotonin neurons also frequently express other neurotransmitters, in particular GABA, glutamate and nitric oxide.⁸

Serotonin production is increased by

• Vitamin D3⁹
  D3 thus increases mood (especially in winter) even in healthy people¹⁰¹¹
  In Germany, 60% of all people suffer from D3 deficiency. Especially in the months of October to April, the natural intensity of sunlight is not sufficient to produce enough D3. Find out more at ⇒ Vitamin D3 In the article ⇒ Vitamins and minerals for ADHD in the section ⇒ Medication for ADHD - Overview of the chapter ⇒ ADHD - treatment and therapy. People with ADHD suffer from D3 deficiency more frequently than average.
• Acetyl-L-carnitine (0.5 g/kg over 25 days) increased the serotonin level in the cortex and the noradrenaline level in the hippocampus of mice.¹² GABA, glutamate and glutamine remained unchanged.
• Zen meditation
  Meditation can increase the brain’s serotonin levels in the long term, not just during the meditation itself.¹³

Serotonin production is reduced by

• Stress¹⁴

2. Control ranges of serotonin¶

• Impulse control¹⁵¹⁶¹⁷
• Situationally appropriate recall of behaviors, especially with regard to emotions¹⁸
  • Together with dopamine
• Controlling the intensity of the stress response¹⁸
  • Together with dopamine
  • 5-HT particularly strongly innervates the stress-integrating structures of the forebrain, including¹⁹
    • Hippocampus
    • PFC
    • Amygdala
    • Hypothalamus
  • Deactivation (lesion) of the raphe nuclei (electrolytically or neurochemically by means of DHT) reduces the responses of the HPA axis to stress through²⁰
    • Restriction of movement (serotonin reduction reduces ACTH secretion by 50 %)²¹
      • In contrast, no reduction in ACTH secretion by 5-HT antagonists in response to swimming stress, ether treatment or endotoxin.
    • Ether²²; different ²¹
    • Administration of the 5-HT antagonist DHT into the PVN in relation to stress caused by ether²²
    • Glutamate administration in the PVN²³
      • Which suggests that serotonin acts directly on the PVN and mediates stress responses there
      • As well as noradrenaline (via α1-adrenoceptors)²⁴
    • Stimulation of the dorsal hippocampus²²
    • Stimulation of the central amygdala²²
      • Whereby serotonin mediates this stress-inhibiting effect in the PVN via 5-HT-2 receptors²⁴
  • Administration of a 5HT2 receptor antagonist into the amygdala inhibits ACTH synthesis in response to light stress²⁵
    • This indicates that serotonin also activates the HPA axis via limbic structures²⁰
• Emotions/emotion control¹⁴²⁶
  • Affect control¹⁸
    • Together with dopamine
  • Mood¹⁴
  • Aggression^15161727
  • Anxiety^15161719
  • Drive¹⁴
  • Mental well-being¹⁴
  • Emotional memory in the amygdala and limbic system¹⁴
• Control of the stimulus intensity²⁸
• Low serotonin levels cause emotional deficits in ADHD²⁹
• Pain perception¹⁵²⁶
• Sleep-wake rhythm³⁰²⁶
• Eating behavior¹⁵²⁶
• Sexual behavior³¹²⁶
• Antisocial personality disorder³²
  Serotonin is important in prenatal brain development. In the early development of the CNS, serotonin influences ¹⁷
• Cell proliferation
• Cell migration
• Cell differentiation

Serotonin increases prolactin and ACTH levels.³³
Serotonin deficiency in the basolateral amygdala causes a decrease in long-term potentiation by increased glutamate and decreased GABA levels in adult female mice exposed to chronic 4-vinylcycloxene diepoxide, which induces anxiety symptoms.³⁴

3. Symptoms of serotonin deficiency¶

Serotonin deficiency in the brain:

• Lack of drive¹⁴
• Sadness¹⁴
• Fears¹⁴³⁵
• Compulsions¹⁴²⁹
• Depressive moods / depression^1429135
• Aggression^161727135
• Stomach/intestinal complaints¹⁴
  • As a messenger substance, serotonin also regulates the nervous system of the digestive tract¹⁴
  • Eating Disorders / Satiety³⁵
• Emotional deficits²⁹
• Inadequate executive functions²⁹
• Learning difficulties²⁹
  • Memory impairment³⁵
• Impulse inhibition problems (if dopamine is also involved)¹³
• Sleep disorders³⁵
  Peripheral (somatic) symptoms of serotonin deficiency:³⁵
• Vasoconstriction (coronary spasms)
• Irritable colon (irritable bowel syndrome)
• Fibromyalgia (sensitivity to pain)
• Scoliosis
• Tendency to thrombosis (platelet aggregation)
• Inflammation (immune dysfunction)
• Melatonin deficiency

Serotonin deficiency in the brain and body:³⁵

• Headache
• Migraine

Serotonin is also involved in schizophrenia.¹
It is striking that serotonin deficiency is associated with internalizing disorders (depression, anxiety) on the one hand and externalizing disorders (aggression, impulse control, antisocial personality disorder) on the other.

4. Serotonin neurons, receptors, transporters¶

4.1. Serotonin receptors¶

The following description of serotonin receptors is based on Jørgensen.³⁶
To date, 7 main groups of serotonin receptors are known, 5-HT-1 to 5-HT-7, which in turn are subdivided into subgroups, e.g. 5-HT2a, 5-HT-2b, 5-TH-2c.

4.1.1. 5-HT1A¶

• In the dorsal raphe nuclei and in the limbic system
• Pre- and postsynaptic³⁷
• Inhibits adenylate cyclase (AC)
  • Inhibition of AC causes memory and learning defects.³⁸
  • Inhibition of AC by binding to the Opiate receptor
  • Inhibition of AC contributes to the development of addiction³⁸
  • Toxins such as cholera toxin and pertussis toxin act by permanently activating adenylate cyclase.³⁸
• Autoreceptor
  • Presynaptically on somatodendritic serotonin neurons in the raphe nuclei³⁹
  • Inhibits the production of serotonin in the raphe nuclei⁴⁰³⁹
• Regulated
  • Mood
    • Depression
    • Suicide
  • Fear
  • Temperature
  • Feeding
  • Movement
  • Aggression (5-HT1A receptor reduced)⁴¹
  • Anorexia (5-HT1A receptor elevated)⁴²
• High densities of postsynaptic 5-HT1A receptors in:⁴¹
  • Hippocampus
  • Septum
  • Amygdala
  • Entorhinal cortex
  • Frontal cortex
• Predominantly inhibiting⁴⁰
• Agonists:
  • 5-CT
  • 8-OH-DPAT
  • RU 24969
• Antagonists:
  • WAY-100635
  • Cyanopindolol
  • Metysergide
• Stress
  • Acute stress decreased the gene expression of the 5-HT1A receptor⁴³ while the gene expression of the 5-HT7 receptor in the CA1 region of the hippocampus increased⁴⁴
  • Corticosterone dose-dependently influences 5-HT1A receptor-mediated responses in the rat hippocampus in vitro and in vivo: activation of only the high-affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated responses, while additional activation of lower-affinity glucocorticoid receptors enhances the effect of 5-HT.⁴⁵
  • Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animals.⁴⁵
• Functional variations in the 5-HT1A gene (HTR1A) appear to be associated with⁴⁶
  • Personality traits of negative emotionality
  • The development of anxiety disorders
• 5-HT1A activation decreases NMDA receptor-mediated currents in pyramidal neurons of the PFC.⁴⁶

4.1.2. 5-HT1B¶

• In substantia nigra, basal ganglia, frontal cortex
• Regulated
  • 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 the development of the thalamic cortex by inhibiting glutamate release.⁴⁶
    • 5-HT filters glutamatergic input from the cortex and thalamus into the basolateral amygdala by activating presynaptic 5-HT1B receptors, not 5-HT1A receptors.⁴⁷
  • Vascular functions
• Predominantly inhibiting⁴⁸
• Agonists:
  • 5-CT
  • RU 24969
• Antagonists:
  • Cyanopindolol

4.1.3. 5-HT2A¶

• In the cortex, hippocampus, caudate nucleus
• Stimulates phospholipase
• Regulated
  • Sleep
  • Motor functions
  • Behavior
• Facilitating predominantly other modes of action⁴⁸
• Agonists:
  • DOI
  • MCPP
  • S-α-methyl-serotonin / Sα-methyl-5-HT
• Antagonists:
  • Metergoline
  • Metysergide
  • Flourobenzoyl
  • Ketanserin
    • Administration of the 5HT2 receptor antagonist ketanserin into the amygdala inhibits ACTH synthesis in response to light stress²⁵
      • This indicates that serotonin also activates the HPA axis via limbic structures²⁰
  • LY 53857
  • Quetiapine, Seroquel (antipsychotic)
• Serotonin acts on 5-HT2A to inhibit the release of dopamine. 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.⁴⁹
• 5-HT2A and 5-HT2C receptors appear to be easily downregulated during chronic activation, but are not subject to upregulation during chronic underactivation. In addition, chronic treatment with serotonin antagonists leads to a paradoxical downregulation of 5-HT2A and 5-HT2C receptors.⁴⁰
• 5-HT2A activation increases NMDA receptor-mediated currents in pyramidal neurons of the PFC((Lesch, Waider (2012): Serotonin in the Modulation of Neural Plasticity and Networks: Implications for Neurodevelopmental Disorders. Neuron VOLUME 76, ISSUE 1, P175-191, OCTOBER 04, 2012 DOI:https://doi.org/10.1016/j.neuron.2012.09.013
• 5-HT1A and 5-HT2A receptors appear to work together in the brain⁵⁰
  • 5-HT2A and 5-HT1A receptors are highly colocalized in the frontal cortex of rodents
  • Balance between postsynaptic 5-HT1A and 5-HT2A receptor activity on neurons can modulate descending excitatory input to limbic and motor structures
  • 5-HT1A and 5-HT2A receptors appear to fine-tune cortical systems that modulate behavioral inhibition and self-control.
  • A relative increase in 5-HT1A receptor activity compared to 5-HT2A receptor binding could potentially contribute to the behavioral inhibition and overcontrol commonly seen in eating disorders
  • An imbalance between the mesial-temporal (amygdala) and cingulate 5HT1A/2A receptors may be a feature of anorexia subgroups and may be related to behavioral inhibition, anticipatory anxiety, or the integration of cognition and mood
  • Together they regulate the inhibition of exploration of new environments

4.1.4. 5-HT2B¶

• Facilitating mainly other modes of action⁴⁸
• Agonists:
  • S-α-methyl-serotonin / Sα-methyl-5-HT

4.1.5. 5-HT2C¶

• In Hypothalamus, Limbic system, Basal ganglia
• Regulated
  • Synaptic plasticity (decisive)⁴⁶
  • Erection of the penis
• Facilitating predominantly other modes of action⁴⁸
• Agonists:
  • DOI
  • MCPP
  • MK 21
  • S-α-methyl-serotonin / Sα-methyl-5-HT
• Antagonists:
  • Metergoline
  • Metysergide
  • Ketanserin
    • Administration of the 5HT2 receptor antagonist ketanserin into the amygdala inhibits ACTH synthesis in response to light stress²⁵
      • This indicates that serotonin also activates the HPA axis via limbic structures²⁰
  • LY 53857
  • SB 242084
  • Quetiapine / Seroquel (antipsychotic)
• 5-HT2A and 5-HT2C receptors appear to be easily downregulated during chronic activation, but are not subject to upregulation during chronic underactivation. In addition, chronic treatment with serotonin antagonists leads to a paradoxical downregulation of 5-HT2A and 5-HT2C receptors.⁴⁰
• 5-HT2C activation increases NMDA receptor-mediated currents in pyramidal neurons of the PFC.⁴⁶

4.1.6. 5-HT3¶

• In pons, brain stem,³⁶ entorhinal cortex, area postrema⁴⁰
• Regulated
  • Vomiting reflex
  • Gastrointestinal movements (e.g. bowel movements)
  • Cardiovascular system
  • Pain perception⁵¹
  • Reward system⁵¹
  • Cognition⁵¹
  • Depression⁵¹
  • Anxiety control⁵¹
• Fast excitatory effect⁴⁸
• Agonists:
  • SR 57227
  • M-CPBG
  • Y-25130
  • Ondansetrone
  • ICS 205-930
• Stimulation of 5-HT3 receptors in the striatum increases endogenous dopamine release.⁶
• 5-HT3R antagonists⁵¹
  • Inhibit the binding of serotonin to the 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

4.1.7. 5-HT4¶

• In cortex, hypothalamus
• Regulated
  • Memory
  • Neurotransmitter release
• Facilitates other active processes⁴⁸
• Agonist:
  • RS 67506
• Antagonists:
  • ICS 205-930
  • RS 2359

4.1.8. 5-HT5A¶

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

4.1.9. 5-HT5B¶

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

4.1.10. 5-HT6¶

• In striatum, hippocampus, cortex
• Regulated
  • Cholinergic system
  • Feeding
• Antagonists:
  • Metergoline

4.1.11. 5-HT7¶

• In Limbic system, suprachiasmatic nucleus, dorsal raphe nuclei
• Regulated
  • Mood
  • Fear
  • Temperature
  • Sleep cycles
• Facilitates other active sequences⁴⁸
• Agonists:
  • 5-CT
  • 8-OH-DPAT
• Antagonists:
  • Metergoline
  • Metysergide
• Stress
  • Acute stress increased the gene expression of the 5-HT7 receptor in the CA1 region of the hippocampus,⁴⁴ while the gene expression of the 5-HT1A receptor decreased⁴³

4.2. Effect of antidepressant medication and treatment on receptors¶

The following presentation is based on Cooper et al.⁵²

4.2.1. 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.

4.2.2. 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

4.2.3. Preynaptic alpha-2 adrenoceptors¶

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

4.2.4. Postsynaptic 5-HT receptors¶

• SSRI: no effect
• MAO-A reuptake inhibitors: no effect or reduced receptor sensitivity due to 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

4.2.5. Change in serotonin levels¶

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

5. Reuptake and breakdown of serotonin¶

5.1. Serotonin transporter¶

Psychosocial stress led to 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.⁵³

The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with an increased risk of ADHD. In carriers of this haplotype, stress exposure and ADHD severity correlate more strongly than in non-carriers. This gene-environment interaction is even stronger if they were also carriers of the homozygous 5-HTTLPR L allele instead of the S allele. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, the parahippocampal gyrus, the intracalcarine cortex and the angular gyrus. This proves that gene variants in the stress response pathway of the HPA axis influence how stress exposure affects the severity of ADHD and brain structure.⁵⁴

5.2. Serotonin degradation¶

Serotonin is broken down by

• MAO-A (main degradation pathway)
• MAO-B
• Aldehyde dehydrogenases
• Acetylation
  • subsequent methylation to melatonin by serotonin-N-acetyltransferase (AANAT) and acetylserotonin-O-methyltransferase (ASMT) with consumption of the methyl group donor S-adenosylmethionine (SAM)

Serotonin is broken down to 5-HIAA (5-hydroxyindolylacetic acid).

6. Serotonin and ADHD¶

ADHD is primarily dopaminergic and secondarily noradrenergic. There is a further, albeit smaller, connection to the serotonergic system.
Serotonin is therefore involved to a lesser extent in ADHD and is said to be more relevant in ADHD-I (without hyperactivity).⁵⁵

Serotonin receptors influence dopamine:⁵⁶

• 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(3) and 5-HT(4) receptors facilitate the release of dopamine
• 5-HT(2C) receptors inhibit the release of dopamine

The dopamine transporters (DAT) located primarily in the striatum, which are overactivated in ADHD, also have a serotonergic affinity in the striatum and therefore also take up serotonin again,⁵⁷ at least when serotonin transporter activity is restricted.⁵⁸
An increase in serotonin caused directly in the striatum also increased the concentration of dopamine in the striatum.⁵⁹

One study of children with ADHD found that increased methylation of the promoter of the serotonin transporter gene correlated with increased hyperactivity and impulsivity and increased impulsive errors in a sustained attention task.⁶⁰ 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 6 years of age⁶¹
Empirically, an effect of serotonergic medication on impulsivity is known.

Taking methylphenidate is said to have an effect on serotonin levels.²⁹

7. Other mental disorders due to malfunctions of the serotonergic system¶

• Depression⁶²⁶³
• Anxiety disorders⁴⁶³
• Schizophrenia⁴⁶³
• Addictive disorders⁴⁶³
• Childhood autism^64651766
• Eating disorders⁶³
  • Anorexia nervosa^646517467
• Vomiting⁶³
• Obsessive-compulsive disorders⁶⁸⁶³
• Cancer⁶³
• Circadian rhythm disturbances⁶³
• Developmental disorders⁶³
• Migraine⁶³
• Neurodegenerative disorders⁶³
• Muscle twitching (myoclonus)⁶³
• Sensitivity to pain⁶³
• Premenstrual syndrome⁶³
• Post-traumatic stress disorder⁶³
• Sexual Disorders⁶³
• Sleep disorders⁶³
• Stress disorders⁶³
  • Activation of serotonin 5-HT-1A receptors in the dorsomedial hypothalamus inhibits stress-induced activation of the HPA axis in rats.⁶⁹

8. Treatment with serotonergic medication (disorders)¶

• Depression⁶⁸
• Obsessive-compulsive disorders⁶⁸
• Anxiety and panic disorders⁶⁸