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

Serotonin (like all monoamines) acts primarily as a volume transmitter. Volume transmitters work in a similar way to volume controls and amplify or inhibit other areas of the brain without directly influencing (synaptic) information processing.² Serotonin shifts the global network dynamics (e.g. impulsive vs. stable, explorative vs. conservative), while dopamine controls the signal strength (which signals are relevant) and noradrenaline influences the signal-to-noise ratio in particular (signal-to-noise ratio; which signals are salient). Metaphorically compared to an orchestra, monoamines as volume transmitters control the volume of entire orchestral blocks (all violins, all trumpets), while synaptic transmission influences the notes played by the individual instruments.
Monoamines, for example, modulate attention by regulating reinforcement at the synapse, which activates or deactivates selected neurons in the attention network. Serotonergic drugs can reduce attention and vigilance
In addition to volume transmission, serotonin is also involved in information processing as a secondary synaptic transmitter.

• 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
    • 4.1.2. 5-HT1D
    • 4.1.2. 5-HT1F
    • 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. Presynaptic 5-HT autoreceptors
    • 4.2.2. Preynaptic alpha-2-adrenergic autoreceptors
    • 4.2.3. Postsynaptic 5-HT hetero-receptors
    • 4.2.4. Change in serotonin levels
• 5. What regulates serotonin
• 6. Reuptake and breakdown of serotonin
  • 6.1. Serotonin transporter
  • 6.2. Serotonin degradation
• 7. Serotonin and ADHD
• 8. Other mental disorders due to malfunctions of the serotonergic system
• 9. 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 thus exert its effect in almost every body tissue³
Serotonin is mainly produced in the cell bodies of neurons of the raphe nuclei.⁴⁵

Humans are home to around 350,000 serotonergic neurons.²

• 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:⁶

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

Tonic serotonin firing occurs at a rhythm of 1 to 5 peaks/second. The frequency of serotonin release is increased by noradrenaline at adrenoceptors and decreased by serotonin at somatodendritic 5-HT-1A autoreceptors.⁷ Somatodendritic and presynaptic serotonin autoreceptors are part of a negative feedback loop that serves to limit excessive serotonin production.⁸ This negative feedback loop is impaired in some disorders.
Serotonin neurons also frequently express other neurotransmitters, in particular GABA, glutamate and nitric oxide.⁹

Serotonin production is increased by

• Vitamin D3¹⁰
  D3 thus increases mood (especially in winter) even in healthy people¹¹¹²
  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.¹³ 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.¹⁴

Serotonin production is reduced by

• Stress¹⁵

2. Control ranges of serotonin¶

• Impulse control¹⁶¹⁷¹⁸
• Hyperactivity
  • But not via the PFC, but via other regions of the brain¹⁹²⁰
• Situationally appropriate recall of behaviors, especially with regard to emotions²¹
  • Together with dopamine
• Controlling the intensity of the stress response²¹
  • Together with dopamine
  • 5-HT particularly strongly innervates the stress-integrating structures of the forebrain, including²²
    • 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 through²³
    • Restriction of movement (serotonin reduction reduces ACTH secretion by 50 %)²⁴
      • In contrast, no reduction in ACTH secretion by 5-HT antagonists in response to swimming stress, ether treatment or endotoxin.
    • Ether²⁵; different ²⁴
    • Administration of the 5-HT antagonist DHT into the PVN in relation to stress caused by ether²⁵
    • Glutamate administration in the PVN²⁶
      • Which suggests that serotonin acts directly on the PVN and mediates stress responses there
      • As well as noradrenaline (via α1-adrenoceptors)²⁷
    • Stimulation of the dorsal hippocampus²⁵
    • Stimulation of the central amygdala²⁵
      • Whereby serotonin mediates this stress-inhibiting effect in the PVN via 5-HT-2 receptors²⁷
  • Administration of a 5-HT2 receptor antagonist into the amygdala inhibits ACTH synthesis in response to light stress²⁸
    • This indicates that serotonin also activates the HPA axis via limbic structures²³
• Emotions/emotion control¹⁵²⁹
  • Affect control²¹
    • Together with dopamine
  • Mood¹⁵
  • Aggression^16171830
  • Anxiety^16171822
  • Drive¹⁵
  • Mental well-being¹⁵
  • Emotional memory in the amygdala and limbic system¹⁵
• Control of the stimulus intensity³¹
• Low serotonin levels cause emotional deficits in ADHD³²
• Pain perception¹⁶²⁹
• Sleep-wake rhythm³³²⁹
• Eating behavior¹⁶²⁹
• Sexual behavior³⁴²⁹
• Antisocial personality disorder³⁵
  Serotonin is important in prenatal brain development. In the early development of the CNS, serotonin influences ¹⁸
• Cell proliferation
• Cell migration
• Cell differentiation

Serotonin increases prolactin and ACTH levels.³⁶
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.³⁷

Serotonergic fibers branch extensively into all areas of the forebrain, including²

• Amygdala
• Hypothalamus
• sensory and motor cortex areas

Descending projections from the 5-HT neurons reach the periaqueductal gray and the posterior horn of the spinal cord.²

Serotonin (like dopamine) affects the cerebral microvasculature by increasing or decreasing blood flow and altering microcirculation in the brain. Serotonin has a major influence on the larger cerebral vessels, causing vasoconstriction or vasodilation and permeability of the blood-brain barrier via its receptors on the endothelial cells and astrocytes that form the neurovascular unit.²

3. Symptoms of serotonin deficiency¶

This section is very simplistic.

Serotonin deficiency in the brain:

• Lack of drive¹⁵
• Sadness¹⁵
• Fears¹⁵³⁸
• Compulsions¹⁵³²
• Depressive moods / depression^1532138
• Aggression^171830138
• Stomach/intestinal complaints¹⁵
  • As a messenger substance, serotonin also regulates the nervous system of the digestive tract¹⁵
  • Eating Disorders / Satiety³⁸
• Emotional deficits³²
• Inadequate executive functions³²
• Learning difficulties³²
  • Memory impairment³⁸
• Impulse inhibition problems (if dopamine is also involved)¹⁴
• Sleep disorders³⁸
  Peripheral (somatic) symptoms of serotonin deficiency:³⁸
• 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:³⁸

• 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 the serotonin receptors is based on Jørgensen.³⁹
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 postsynaptic⁴⁰¹⁹
  • Systemic administration of the 5-HT1A receptor agonist 8-OHDPAT, increased impulsive choice, dependent on dopamine in the nucleus accumbens, presumably via an effect on presynaptic autoreceptors that reduces serotonin release⁴¹
  • Administration of 8-OHDPAT to the orbitofrontal cortex reduced impulsive decision making, possibly due to binding to postsynaptic receptors⁴²
• Inhibits adenylate cyclase (AC)
  • Inhibition of AC causes memory and learning defects.⁴³
  • Inhibition of AC by binding to the Opiate receptor
  • Inhibition of AC contributes to the development of addiction⁴³
  • Toxins such as cholera toxin and pertussis toxin act by permanently activating adenylate cyclase.⁴³
• Dopamine
  • Increasing in PFC and substantia nigra (local)¹⁹
  • Reducing in the striatum and nucleus accumbens¹⁹
• Autoreceptor
  • Presynaptically on somatodendritic serotonin neurons in the raphe nuclei⁴⁴
  • Inhibits the production of serotonin in the raphe nuclei⁴⁵⁴⁴
• Regulated
  • Mood
    • Depression
    • Suicide
  • Fear
  • Temperature
  • Feeding
  • Movement
  • Aggression (5-HT1A receptor reduced)⁴⁶
  • Anorexia (5-HT1A receptor elevated)⁴⁷
• High densities of postsynaptic 5-HT1A receptors in:⁴⁶
  • Hippocampus
  • Septum
  • Amygdala
  • Entorhinal cortex
  • Frontal cortex
• Predominantly inhibiting⁴⁵
• Agonists:
  • 5-CT
  • 8-OH-DPAT
  • RU 24969
• Antagonists:
  • WAY-100635
  • Cyanopindolol
  • Metysergide
• Stress
  • Acute stress decreased the gene expression of the 5-HT1A receptor⁴⁸ while the gene expression of the 5-HT7 receptor in the CA1 region of the hippocampus increased⁴⁹
  • 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.⁵⁰
  • Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animals.⁵⁰
• Functional variations in the 5-HT1A gene (HTR1A) appear to be associated with⁵¹
  • Personality traits of negative emotionality
  • The development of anxiety disorders
• 5-HT1A activation decreases NMDA receptor-mediated currents in pyramidal neurons of the PFC.⁵¹

4.1.2. 5-HT1B¶

• In substantia nigra, basal ganglia, frontal cortex
• Dopamine
  • Reducing in striatum, nucleus accumbens and substantia nigra (local)¹⁹
• 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.⁵¹
    • 5-HT filters glutamatergic input from the cortex and thalamus into the basolateral amygdala by activating presynaptic 5-HT1B receptors, not 5-HT1A receptors.⁵²
  • Vascular functions
• Predominantly inhibiting⁵³
• Agonists:
  • 5-CT
  • RU 24969
• Antagonists:
  • Cyanopindolol

4.1.2. 5-HT1D¶

Influence on dopamine unknown. To date, selective 5-HT1D agonists have not been investigated for their effects on dopamine.¹⁹

4.1.2. 5-HT1F¶

Influence on dopamine unknown. To date, selective 5-HT1F agonists have not been investigated for their effects on dopamine.¹⁹

4.1.3. 5-HT2A¶

• In the cortex, hippocampus, caudate nucleus
• Stimulates phospholipase
• Dopamine
  • Increasing in PFC, striatum and nucleus accumbens¹⁹
• Regulated
  • Sleep
  • Motor functions
  • Behavior
• Predominantly excitatory⁵³
• 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 stress²⁸
      • This indicates that serotonin also activates the HPA axis via limbic structures²³
  • LY 53857
  • Quetiapine, Seroquel (antipsychotic)
• Serotonin acts on 5-HT2A to inhibit the release of dopamine. 5-HT2A antagonists prevent this.
• Serotonin supports the excitatory effects of glutamate in the nucleus motorius nervi facialis, which controls motor processes and facial expressions. This support is prevented by 5-HT2 antagonists.⁵⁴
• 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.⁴⁵
• 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 brain⁵⁵
  • 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¶

• Predominantly excitatory⁵³
• Dopamine
  • Increasing in nucleus accumbens¹⁹
  • Reducing in PFC¹⁹
• Agonists:
  • S-α-methyl-serotonin / Sα-methyl-5-HT

4.1.5. 5-HT2C¶

• In hypothalamus, limbic system, basal ganglia
• Dopamine
  • Reducing in PFC, striatum and nucleus accumbens¹⁹
• Regulated
  • Synaptic plasticity (decisive)⁵¹
  • Erection of the penis
• Predominantly excitatory⁵³
• 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 stress²⁸
      • This indicates that serotonin also activates the HPA axis via limbic structures²³
  • 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.⁴⁵
• 5-HT2C activation increases NMDA receptor-mediated currents in pyramidal neurons of the PFC.⁵¹

4.1.6. 5-HT3¶

• In the pons, brain stem,³⁹ entorhinal cortex, area postrema⁴⁵
• Dopamine
  • Increasing in PFC, striatum and nucleus accumbens¹⁹
• Regulated
  • Vomiting reflex
  • Gastrointestinal movements (e.g. bowel movements)
  • Cardiovascular system
  • Pain perception⁵⁶
  • Reward system⁵⁶
  • Cognition⁵⁶
  • Depression⁵⁶
  • Anxiety control⁵⁶
• Fast excitatory effect⁵³
• Ligand-gated ion channel¹⁹
  • Most other 5-HT receptors are metabotropic (G-protein-coupled), which activate certain second messenger systems
• Agonists:
  • SR 57227
  • M-CPBG
  • Y-25130
  • Ondansetrone
  • ICS 205-930
• Stimulation of 5-HT3 receptors in the striatum increases endogenous dopamine release.⁷
• 5-HT3R antagonists⁵⁶
  • 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
• Dopamine
  • Increasing in striatum¹⁹
• Regulated
  • Memory
  • Neurotransmitter release
• Excitatory⁵³
• Agonist:
  • RS 67506
• Antagonists:
  • ICS 205-930
  • RS 2359

4.1.8. 5-HT5A¶

• In cortex, hippocampus, hypothalamus
• Dopamine
  • Effect on dopamine unknown¹⁹
• Inhibitory⁵⁷
• 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
• Dopamine
  • Effect on dopamine unknown¹⁹
• Inhibitory⁵⁷
• Regulated
  • Unknown

4.1.10. 5-HT6¶

• In striatum, hippocampus, cortex
• Dopamine
  • WAY-181187 (selective 5-HT6 agonist) in high dose⁵⁸
    • Reduced dopamine in the PFC and striatum; a 5-HT6 antagonist reversed this in the striatum
      • The GABA-A receptor antagonist bicuculline (10 µM) attenuated this effect
    • Left dopamine unchanged (but increased GABA) in dorsal hippocampus, striatum and amygdala
  • ST1936 (selective 5-HT6 agonist) increased dopamine in the PFC and the nucleus accumbens shell and somewhat weaker in the nucleus accumbens core⁵⁹
• Excitatory⁵⁷
• Regulated
  • Cholinergic system
  • Feeding
• Antagonists:
  • Metergoline

4.1.11. 5-HT7¶

• In limbic system, suprachiasmatic nucleus, dorsal raphe nuclei
• Dopamine
  • SB-269970 (selective 5-HT7 antagonist)
    • Did not affect MK-801-induced dopamine levels in the PFC⁶⁰
    • Inhibited the neuronal activity of dopamine neurons after amphetamine treatment in the VTA, but not in the substantia nigra pars compacta⁶¹
• Regulated
  • Mood
  • Fear
  • Temperature
  • Sleep cycles
• Excitatory⁵³
• 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,⁴⁹ while the gene expression of the 5-HT1A receptor decreased⁴⁸

4.2. Effect of antidepressant medication and treatment on receptors¶

The following presentation is based on Cooper et al.⁶²

4.2.1. Presynaptic 5-HT autoreceptors¶

• 5-HT autoreceptors in general
  • 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
• 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. Preynaptic alpha-2-adrenergic autoreceptors¶

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

4.2.3. Postsynaptic 5-HT hetero-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

4.2.4. Change in serotonin levels¶

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

5. What regulates serotonin¶

Serotonergic nuclei receive significant direct monosynaptic inputs from multiple areas of the brain that exert inhibitory and excitatory influences on the serotonergic system:²

• glutamatergic inputs from
  • PFC
  • Haveula
  • Hypothalamus
  • Medulla
• GABAergic inputs from
  • Striatum
  • local circuits in the dorsal raphe

6. Reuptake and breakdown of serotonin¶

6.1. 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. The volume of gray matter in the frontal pole and anterior cingulate gyrus mediated the association of this gene-environment interaction with the number of ADHD symptoms.⁶³

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.⁶⁴

6.2. 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).

7. Serotonin and ADHD¶

ADHD is primarily dopaminergic and secondarily noradrenergic. There is a connection to the serotonergic system, albeit a relatively minor one.⁶⁵⁶⁶ Just as dopamine and noradrenaline do not act independently of each other and influence each other, dopamine and noradrenaline are also intertwined with the serotonin system.⁵⁷
Among 182 identified possible comorbidities to ADHD, 135 (74.2%), of which 91 were psychiatric and 44 somatic, were found to have evidence of serotonergic pathophysiology. The evidence for a serotonergic role in the pathophysiology of a given comorbidity was generally moderate to high or high⁶⁷
Serotonin is nevertheless involved in ADHD to a lesser extent and is said to be more relevant in ADHD-I (without hyperactivity).⁶⁸

To date, there are no serotonergic medications for ADHD. Empirically, an effect of serotonergic medication on impulsivity is known. Taking methylphenidate is said to have an effect on serotonin levels.³² The development of many SERT reuptake inhibitors has been discontinued due to their limited effect on ADHD.⁵⁷

Studies of serotonin measurements in the brain (in animals) or CSF measurements (in humans) were more likely to find serotonin deficits in ADHD, while studies of platelet measurements were more likely to report serotonin excess in ADHD.⁵⁷

People with ADHD showed:⁶⁹
- a reduced blood serotonin level in the morning
- a serotonin daytime profile that differs from that of unaffected people, especially at night
- increased blood melatonin levels in the morning
- increased blood melatonin levels in ADHD-HI
- MPH
- did not affect the blood serotonin level
- reduced 6-S-aMT excretion
- reduced the morning melatonin level

Children with ADHD showed⁷⁰

• Hemoglobin level significantly reduced
• Blood serotonin significantly reduced
• IgE value increased
• Eosinophil count increased

There were 89 children:⁷¹

• free HT-5 in plasma
  • significantly increased free 5-HT plasma levels in ADHD, without differences between presentation forms
  • with ADHD severity, free 5-HT blood levels increased further
  • Increase in free 5-HT plasma levels by 0.1 µmol/L increased the risk of ADHD by 71
  • AUC for free 5-HT:
    • 76 % for ADHD diagnosis
    • 93 % for moderate/severe ADHD
  • free 5-HT also increased with overweight/obesity
• platelet 5-HT plasma levels tend to be reduced in ADHD

One study found evidence of reduced tryptophan uptake across the blood-brain barrier in boys with ADHD. Tyrosine uptake was unchanged.⁷²

Dogs with ADHD showed reduced serotonin and dopamine blood levels.⁷³

Serotonin receptors influence dopamine:⁷⁴

• 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,⁷⁵ at least when serotonin transporter activity is restricted.⁷⁶
An increase in serotonin caused directly in the striatum also increased the concentration of dopamine in the striatum.⁷⁷
The behavioral deficits typical of ADHD in DAT-KO mice (action impulsivity, hyperactivity, increased reward motivation) are reversed by the selective serotonin 2A receptor antagonist M100907⁷⁸
DAT-KO rats showed⁷⁹

• profound dysregulation of dopamine neurotransmission in the striatum, midbrain, PFC, hippocampus, medulla oblongata and spinal cord
• significant changes in the mRNA production of enzymes of the monoamine metabolism
• a remarkable change in the tissue level of serotonin, especially in the cerebellum and spinal cord

Mice with the Ala559Val-DAT variant exhibit significant serotonergic plasticity involving enhanced 5-HT2C signaling that acts independently of striatal DA release and can suppress the activity of cocaine-sensitive motor circuits.⁸⁰

In SHR, a 5-HT1A agonist (ipsapirone) as well as a 5-HT2A antagonist (MDL 100907) improved ADHD symptoms. The improvement correlated (also with guanfacine) with⁸¹

• upregulation of 5-HT2A receptors in the PFC, striatum and substantia nigra
• upregulation of 5-HT1A in PFC and substantia nigra
• the downregulation of D1R
  • by 5-HT1A agonists (ipsapirone) in PFC, striatum and substantia nigra
  • by 5-HT2A antagonist (MDL 100907) in PFC and striatum
  • by guanfacine in PFC and substantia nigra

In children with ADHD, 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.⁸² Decreased methylation of the serotonin transporter gene (and the DRD4 gene) in newborns correlated with increased ADHD symptoms at 6 years of age⁸³

People with ADHD showed:⁸⁴

• 5-HTTLPR “L” alleles more frequent
• 5-HTTLPR “L/L” genotype more frequent
• 5-HIAA level reduced
• SERT mRNA expression increased
• Behavioral problems and hyperactivity correlated with 5-HTTLPR “S” alleles and the “S/S” genotype
• Executive deficits correlated with “L” alleles

Boys with ADHD showed no changes in noradrenaline, dopa and lipid levels in the blood in relation to hyperactivity, impulsivity, poor concentration or aggressiveness. Only blood serotonin levels tended to be slightly lower in more severe ADHD.⁸⁵

Platelet serotonin 5-HT(2A) receptors were unchanged in ADHD.⁸⁶

The serotonin level in the blood platelets (thrombocytes):⁸⁷

• was unchanged in children with ADHD
• was unchanged between boys and girls
• correlated with impulsivity, but not with inattention or hyperactivity

NHL rats (rats with neonatal habenula lesion) show⁸⁸

• ADHD symptoms
  • Hyperlocomotion
  • Impulsiveness
  • Attention deficits
• Changes in DA and 5-HT concentrations in the tissue of some (not all) mesocorticolimbic regions
• Improvement of ADHD-typical behavioral changes and normalization of the NHL-induced imbalance between DA and 5-HT in several brain regions by simultaneous pharmacological manipulations of the DA and 5-HT systems with Astragalus membranaceus and its active ingredient formononetin

The hormonal response to fenfluramine is an index of serotonergic function.
Reduced response to FEN provocation predicted the development of antisocial personality disorder 9 years later.⁸⁹
In aggressive boys with a family history of aggressive behavior, the prolactin response to FEN provocation was significantly lower than in aggressive boys without a family history of aggressive behavior.⁹⁰

Elevated tryptophan levels in the umbilical cord blood at birth correlated with an increased risk of ADHD⁹¹, as did free tryptophan blood levels with the severity of hyperactivity.⁹²

In children with ODD, the postsynaptic 5-HT(1B/1D) receptor appears to be functionally more sensitive.⁹³

There was no difference in mean whole blood serotonin levels in ADHD children with or without comorbid CD or ODD.⁹⁴

Although ADHD drugs such as amfetamine, methylphenidate and atomoxetine have a primarily dopaminergic and secondarily noradrenergic effect, they also have a serotonergic effect (see there in each case). Although atomoxetine inhibits SERT, it did not increase extracellular serotonin levels in the PFC⁹⁵, the striatum⁹⁶ or the hippocampus⁹⁷

The SERT binding potential is also relevant in ADHD⁵⁷

• in the posterior cingulate gyrus⁹⁸
• in the Cuneus⁹⁸
• in the Precuneus⁹⁸
• low SERT binding potential in platelets correlated with cognitive impulsivity (distractibility)⁹⁹
• increased SERT binding potential in platelets correlated with behavioral disorders⁹⁹

Other studies found no evidence of changes in SERT in ADHD.^100101102

Some studies have found anomalies in the reduction of serotonin in relation to ADHD, although the evidence is rather low⁵⁷

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

• Depression¹⁰³¹⁰⁴
• Anxiety disorders⁵¹⁰⁴
• Schizophrenia⁵¹⁰⁴
• Addictive disorders⁵¹⁰⁴
• Childhood autism^10510618107
• Eating disorders¹⁰⁴
  • Anorexia nervosa^105106185108
• Vomiting¹⁰⁴
• Obsessive-compulsive disorders¹⁰⁹¹⁰⁴
• Cancer¹⁰⁴
• Circadian rhythm disturbances¹⁰⁴
• Developmental disorders¹⁰⁴
• Migraine¹⁰⁴
• Neurodegenerative disorders¹⁰⁴
• Muscle twitching (myoclonus)¹⁰⁴
• Sensitivity to pain¹⁰⁴
• Premenstrual syndrome¹⁰⁴
• Post-traumatic stress disorder¹⁰⁴
• Sexual Disorders¹⁰⁴
• Sleep disorders¹⁰⁴
• Stress disorders¹⁰⁴
  • Activation of serotonin 5-HT-1A receptors in the dorsomedial hypothalamus inhibits stress-induced activation of the HPA axis in rats.¹¹⁰

9. Treatment with serotonergic medication (disorders)¶

• Depression¹⁰⁹
• Obsessive-compulsive disorders¹⁰⁹
• Anxiety and panic disorders¹⁰⁹
• Hyperactivity also outside of ADHD^111112113114
• The SSRI citalopram did not resolve hyperactivity in SHR.¹¹⁵