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Histamine

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Histamine

Histamine is a biogenic amine and acts as a neurotransmitter and hormone. It could have a relevant significance in ADHD.
Histamine regulates the release of dopamine. Almost all ADHD medications increase histamine. Histamine appears to be reduced in ADHD.
H3 antagonists, which increase histamine as a result, have a beneficial effect on various ADHD symptoms as well as on social symptoms in ASD. ADHD and ASD very often occur comorbidly. Histamine could also play a role in the disorders of the day-night rhythm that are common in ADHD.

Histamine is toxic in high doses. Spoiled fish triggers histamine poisoning within 20 minutes.
Histamine is a potent inflammatory mediator with pleiotropic effects that is involved in the regulation of innate and adaptive immunity.1

1. Development of histamine

1.1. Pathway of histamine formation

Conversion of the amino acid L-histidine to histamine by

  • Pyridoxal phosphate-dependent oxidative decarboxylation using the enzyme histidine decarboxylase ( L-histidine decarboxylase, EC 4.1.1.22) or
  • Non-specific aromatic L-amino acid decarboxylase

α-fluoromethyl-histidine suppresses histamine synthesis.2

Histamine is produced by mast cells, basophils, thrombocytes and some neurons, stored in vesicles and released upon stimulation.

1.2. Site of histamine formation in the brain

Only a few nerve cells in the brain produce histamine.3 Synthesis of histamine and storage in vesicles of:4

  • Tuberomammillary nucleus (TMN) of the hypothalamus

    • Main site of the histamine neurons
      • Human: 64,000 histaminergic neurons
      • Rats: 4,600 in the brain in total
    • TMH cells produce GABA as well as histamine.
    • Project to the cerebral cortex
    • Significantly regulate arousal and alertness.
    • There appear to be 5 groups of TMN cells that differ in the expression of the H3 receptor and in the co-expression of GABA, among other things
    • Deactivation of TMN by the GABA agonist muscimol leads to prolonged REM-free sleep; optogenetic activation of a subpopulation of TMN neurons induces wakefulness5
    • The activity of TMN neurons varies depending on the waking state: it is low in the calm waking state, moderate in the active waking state and highest in the alert waking state.6
    • Histamine maintains alertness through direct projections of TMN cells to the thalamus and cortex and indirectly through activation of cholinergic (via H1 and H2 receptors)7, GABAergic89 and noradrenergic cells (in the locus coeruleus).10
  • Mastocytes (mast cells)

    • Contain considerable amounts of histamine from the brain
    • Are only found in
      • Thalamus
      • Hypothalamus
      • Dura mater
      • Leptomeninx
      • Choroid plexus
  • Microglia

  • Microvascular endothelial cells

  • Projections are widely used, e.g. in4

    • Cerebrum
    • Cerebellum
    • Posterior pituitary gland
    • Spinal cord

1.3. Histamine in the body (peripheral)

Synthesis of histamine and storage in vesicles peripherally in4

  • Mast cells
  • Basophils (basophilic granulocytes, a small subgroup of white blood cells (leukocytes))
  • Epidermal cells
  • Gastric mucosa
    • Enterochromaffin-like cells, control the release of gastric acid

Peripheral histamine is mainly involved in1

  • local immune reactions
  • Digestive system

2. Storage of histamine

Storage bound to heparin in vesicles, primarily in

  • Mast cells
  • Basophilic granulocytes
  • Mucous membranes
  • Bronchi
  • Gastrointestinal tract

3. Release of histamine

Release from vesicles by

  • IgE-mediated allergic reactions of the “immediate type” (type I)
  • Complement factors (e.g. in the case of endotoxin-induced shock)

4. Breakdown / reuptake of histamine

Histamine degradation takes place

  • extracellular (especially food histamine)
    • by means of diamine oxidases (DOA, extracellular; former name: histaminase) and aldehyde oxidases (intracellular) to imidazolylacetic acid.
    • After ribosylation excretion by kidney.
  • intracellular (e.g. in the liver)
    • by histamine methylation (ring methylation by histamine N-methyltransferase)
    • Only a small proportion of histamine degradation
    • In the case of HNMT deficiency, degradation by DAO can increase.

4.1. Dismantling

4.1.1. Degradation in the brain (CNS) primarily due to HNMT

Histamine is inactivated in the brain by the enzyme histamine N-methyltransferase (intracellular) to inactive Nτ-methylhistamine.
HNMT (EC 2.1.1.8) catalyzes the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to histamine, resulting in Nτ-methylhistamine and S-adenosyl-l-homocysteine.11 Nτ-methylhistamine is oxidatively degraded via monoamine oxidases, diamine oxidases (extracellular) and aldehyde oxidases (intracellular) to Nτ-methylimidazolylacetic acid.12

HNMT is found in the human brain in neurons and glial cells in:11

  • Cerebellum (high quantity)
  • frontal cortices (medium quantity)
  • parietal cortices
    • Hippocampus (average amount)
    • Caudate nucleus (medium quantity)
  • temporal cortices
  • occipital cortices

In humans, HNMT shows binding affinity to:11

  • S-Adenosyl-l-methionine (SAM) (Km: 2.0-6.2 µM)
  • Histamine (Km: 13-20 µM)

HNMT knockout mice showed:13

  • drastically increased histamine levels in the brain, intracellular and extracellular
  • other monoamines in the brain unchanged
  • high aggressiveness due to excessive H2R activation
  • reduced movement activity in home cages
    • probably due to disturbed sleep-wake cycle caused by excessive H1R activation
  • no anxiety-like behavior
  • no depression-like behaviors
  • no memory impairment
  • no motor impairments

Inhibitors of HNMT:11

  • Metoprine
    • Blood-brain-barrier-crossing
    • Antinociception
    • Suppression of energy absorption
    • hyperglycemic effect
    • Improvement of cognitive functions
    • antiepileptic effect
    • Attenuation of methamphetamine-induced behavioral problems
    • Inhibition of dihydrofolate reductase
    • Reduction in cellular folate metabolism, which inhibits cell growth
  • SKF91488
    • has difficulty crossing the blood-brain barrier
  • Amodiaquine
  • Chloroquine
  • Dimaprite
  • Etoprine
  • Quinacrine
  • Tacrine

4.1.2. Degradation in the body primarily by diamine oxidase (DAO, histaminase)

Diamine oxidase (DAO, also known as histaminase) is a homodimeric protein and is encoded by the AOC1 gene. DAO is mainly found in the microvilli of enterocytes.
DAO oxidatively deaminates various amines, among others:11

  • Histamine (Km: 19 µM in the intestine)14
  • Cadaverine (1,5-diaminopentane)
  • Putrescine (Km: 83 µM)
  • N Tau-methylhistamine (N-methylhistamine, 1-methylhistamine) (Km: 97 µM)
  • Spermidine
  • Benzylamine (low)
  • Methylamine (low).
    (Km: Michaelis constant; substrate concentration at which the reaction rate becomes half-maximum)

DAO is mainly expressed in the digestive tract, where it serves to detoxify histamine from food in order to reduce histamine uptake by enterocytes. If DAO is impaired, this results in a higher histamine uptake and thus an increased histamine blood level.11
DAO is also expressed to a lesser extent in the kidneys, placenta15 and lungs. DAO plays little to no role in the brain.16
The optimum pH value for the breakdown of histamine by DAO is 6.4 to 6.6.14
DAO dysfunctions appear to play a role in various diseases.

In the intestine:

  • Histamine intolerance17
  • ischemic bowel syndrome14
  • Mesenteric infarction14
  • Ulcerative colitis14

In the placenta15

  • Gestational diabetes
  • threatened and missed miscarriages
  • trophoblastic disorders.

4.2. Resumption

Astrocytes and endothelial cells play an important role in histamine excretion.1819
The plasma membrane monoamine transporter (PMAT) and the organic cation transporter 3 (OCT3) transport histamine in humans mainly into astrocytes, where it is metabolized by HNMT.20
PMAT and OCT 1 to 3 are polyspecific transporters. They transport various monoamines, including serotonin, dopamine, noradrenaline and histamine.
In contrast to the catecholamines (e.g. DAT, NET) and serotonin (SERT), no high-affinity “uptake 1” transporter has been identified for histamine to date. While uptake 1 transporters generally show strong affinity with Km values below 5 μM, the affinity of uptake 2 transporters is considerably weaker with Km values Km (here: for histamine) of at least 100 μM.20 PMAT and OCT 1 to 3 are therefore low-affinity “uptake 2” transporters.21 Nevertheless, “uptake 2” transporters such as OCR3 contribute to reuptake not only at high concentrations, but at any concentration.

4.2.1. Plasma membrane monoamine transporter (PMAT)

The main description of the PMAT can be found at Dopamine reuptake by the plasma membrane monoamine transporter (PMAT) in the article Dopamine reuptake, dopamine degradation

Discovered in 2004,22 PMAT (encoded by the SLC29A4 gene) is widely distributed in the human brain and appears to be involved in dopamine and serotonin clearance in addition to histamine reuptake.11
PMAT is significantly more involved in histamine reuptake than OCT319 in human astrocytes.20
Whether PMAT reuptakes histamine not only in astrocytes but also presynaptically in histamine neurons remains to be seen.
Km for histamine is at least 100 μM.20
PMAT gene polymorphisms with reduced transport activity for the monoamines serotonin and dopamine as well as the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) correlate with Autism Spectrum Disorders (ASD).23
PMAT-KO mice (which therefore have a PMAT deficiency) show neither a strong change in brain histamine levels nor behavioral abnormalities outside of stressful situations.2411

4.2.2. Cation transporter 3, Organic cation transporter 3 (OCT3, SLC22A3)

The main presentation of OCT can be found at Dopamine reuptake by organic cation transporters (OCT) In the article Dopamine reuptake, dopamine degradation

Km of OCT3 for histamine is at least 100 μM.20
Whether OCT3 reuptakes histamine not only in astrocytes but also presynaptically in histamine neurons remains to be seen.20

4.4.3. Cation transporter 2, Organic cation transporter 2 (OCT2, SLC22A2)

In addition to OCT3, the organic cation transporter 2 (OCT2, SLC22A2) also reuptakes histamine, but was not found in human astrocytes,19 but in the human brain, as well as OCT1 (SLC22A1), OCTN1 (SLC22AN1) and OCTN2 (SLC22AN2).25
The human OCT2 transports:20

  • Cations
    • Tetraethylammonium
    • 1-Methyl-4-phenylpyridinium (MPP)
  • Medication
    • Cimetidine (H2R antagonist)
  • Neurotransmitters
    • Histamine
    • Acetylcholine
    • Dopamine
    • Noradrenaline
    • Serotonin
      OCT2 is found in the brain at presynaptic nerve endings in20
  • Cortex
  • Hippocampus
  • Thalamus
  • Hypothalamus
  • dorsal raphe nucleus
  • Locus coeruleus

Km for histamine:20

  • 111 μM (mouse)
  • 0.89 mM (rat)
  • 0.94 mM to 1.3 mM (human).

5. Histamine receptors

Histamine can further influence

  • Learning and memory processes26
  • Thermoregulation26
  • Satiety (due to histamine in the brain)27
  • Energy consumption is increased by histamine in the hypothalamus26
  • Glucose uptake and insulin function in the body26
  • Feeding behavior is reduced by histamine in the hypothalamus26 while histamine generally increases arousal for feeding27
  • Improvement of motor balance and motor coordination via H2 receptors in the cerebellum28
  • Increases motor activity/exploratory behavior via H2 receptors, not via H1 receptors2
  • Increases anxiety primarily via H2 receptors and concomitantly via H1 receptors2

5.1. H1 histamine receptor

  • About as often as H2R4
    • Nevertheless functionally significant as H2R
  • Postsynaptic20
  • Low histamine affinity1
  • Is expressed in various cells, including mast cells1
  • Involved in type 1 hypersensitivity reactions1
  • Coupled to4
    • Gq/11 protein
    • Phospholipase C
      • Promotes inositol trisphosphate (IP3)-dependent Ca2+ release from intracellular Ca2+ stores
      • Is directly involved in the formation of diacylglycerol
        • Activates protein kinase C, which phosphorylates intracellular proteins
    • Activated4
      • AMP kinase
      • Nuclear factor Kappa B
      • Nitric oxide synthases
      • Phospholipase A2 (PLA2)
        • Induces the formation of arachidonic acid
  • Regulatory area
    • Systemic vasodilation (vasodilatation)
    • Reddening of the skin
    • Day-night rhythm
      • Mice without H1 receptors have a disturbed day-night rhythm and are not awakened by H3 antagonists.3
      • Sleep29
    • Vomiting
    • Bronchoconstriction
    • Neurotransmission
    • Possibly antidepressant
    • Possibly anticonvulsant
    • Possibly appetite suppressant
  • Agonists
    • Histamine
    • Histaprodifen
  • Antagonists
    • Loratadine
    • Cetirizine
    • Fexofenadine
    • Doxylamine
    • Diphenhydramine
    • Chlorpheniramine (antagonist / inverse agonist)30

5.2. H2 histamine receptor

  • About as often as H1R4
    • Nevertheless functionally less significant than H1R
  • Postsynaptic20
  • Low histamine affinity1
  • Coupled to4
    Gs
  • Stimulates adenylyl cyclase4
    • Which increases intracellular cyclic adenosine monophosphate (cAMP)
      • Which activates protein kinase A (PKA) and the transcription factor cAMP response element-binding protein (CREB)
  • Blocks the Ca2+-activated potassium conductivity4
  • Inhibits PLA24
  • Inhibits the release of arachidonic acid4
  • Regulatory area
    • Is mainly involved in the cytokine production of Th1 lymphocytes1
    • Gastric acid secretion
    • Reflex tachycardia
  • Agonists
    • Histamine
    • Betazol
  • Antagonists
    • Cimetidine
    • Famotidine
    • Ranitidine
    • Roxatidine

5.3. H3 histamine receptor

  • High histamine affinity1
  • Short
    • Is found on histaminergic neurons (autoreceptor, less common)420
    • On
      • Soma
      • Dendrites
      • Axons
    • Negative feedback to inhibit histamine synthesis and the release of histamine
  • Long
    • Is found on other neurons, including glutamate, acetylcholine, GABA (heteroreceptor), large majority4
      • Other sources report H3R only as an autoreceptor20
    • On axons of the basal ganglia
      • Especially in the dorsal and ventral striatum
      • It is unclear to us: why postsynaptically on axons (the sending neuron parts) and not on dendrites (the receiving ones)?
  • H3R as well as HNMT, H1R and H2R appear to be frequently expressed in ASA.31
  • Signal paths:4
    • Coupled to Gi/o
      • Inhibits adenylyl cyclase and activated Ca2+ channels
      • Controls histamine synthesis and neurotransmitter release
    • Inhibition of the Na+/H+ pump
    • Amplification of G-protein-driven inwardly rectifying K+ channels
    • Activation of phospholipase C
    • Controls mitogen-activated protein kinase (MAPK) pathway
    • Controls phosphatidylinositol 3-kinase (PI3K) pathway
  • Regulatory area
    • Neurotransmission
      Regulation of the release of
      • Histamine (autoregulation)
        • H3 antagonists increase the release of histamine2
      • Acetylcholine
      • Noradrenaline
      • Serotonin
      • Dopamine
      • Glutamate
    • Regulation of the circadian rhythm
    • Involved in the function of the blood-brain barrier1
  • Agonists
    • Histamine
    • Α-Methylhistamine
    • Immepip
    • Imetit
  • Antagonists / inverse agonists
    increase the activity of histaminergic neurons in the brain and thus promote arousal and cognition32
    • Ciproxifan
    • Thioperamide
      • Parkinson’s disease33
      • Increases motor activity / exploratory behavior2
      • Increases anxiety2
    • Pitolisant (antagonist/inverse agonist); Wakix® (pitolisanth hydrochloride)33, selective H3R antagonist/inverse agonist34
      • Narcolepsy, sleep disorders
        • In narcolepsy, a significantly reduced histamine level was found in the brain35
      • No effects on:34
        • Striatal dopamine
          • Other than AMP, Modafinil, Solriamfetol
        • Locomotion
          • Even attenuated hyperlocomotion triggered by modafinil or solriamfetol
        • Food intake
    • H3RA 2-1833
      • Epilepsy
    • Clobenpropit (antagonist, inverse agonist)
      • Apparently directly inhibited dopamine reuptake in vitro, as well as somewhat weaker norepinephrine reuptake in striatal and cerebro-cortical synaptosomes36
    • Iodophenpropit
      • Apparently directly inhibited dopamine reuptake in vitro, as well as somewhat weaker norepinephrine reuptake36
    • ABT-288 (selective H3R antagonist)37
    • ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] (selective H3R antagonist)3839
      • Showed full efficacy in the five-time inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg
      • Full efficacy in the social recognition memory model in adult rats at 0.01 mg/kg.
      • Did not stimulate the locomotor system
      • Minor side effects
    • A-349821 (((4’-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone))40
    • A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone]41
      • improved cognitive performance in a five-trial avoidance test for rat pups (10 mg/kg); similar to thioperamide (10 mg/kg), ciproxifan (3 mg/kg) and GT-2331 (1 mg/kg)42
      • social memory in the adult rat significantly improved by 3 and 10 mg/kg42
    • A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide]41
      • improved cognitive performance in a five-trial avoidance test for rat pups (3 mg/kg); similar to thioperamide (10 mg/kg), ciproxifan (3 mg/kg) and GT-2331 (1 mg/kg)42
      • significantly improved social memory in the adult rat at 1 and 3 mg/kg42
    • GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg)42
    • Enerisant (competitive antagonist, inverse agonist)32
      • [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)Methanone monohydrochloride (enerisant hydrochloride)
      • Binds dose-dependently and selectively to the histamine H3 receptor in the frontal cortex
      • Increased extracellular histamine levels in the posterior hypothalamus
      • Increased dopamine and acetylcholine levels in the medial prefrontal cortex
      • Improved cognition
      • Reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test at 0.03 to 0.3 mg/kg, p.o.
      • Wakefulness-inducing effects at 3 to 10 mg/kg, p.o.
    • ST-713
      • H3 antagonist (Ki = 1.21 nM)
      • D2 antagonist (Ki = 41 nM)
      • D3 antagonist (Ki = 50 nM)
      • Low affinity to other receptors
        • H1 (Ki = 205 nM)
        • H4 (Ki = 210 nM)
        • D1 (Ki = 232 nM)
        • D5 (Ki = 105 nM)
      • Reduced autistic behavior in male BTBR T+tf/J mice.4344
        • ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine) improved at 2.5, 5 and 10 mg/kg, i.p. dose-dependent
          • social deficits
          • repetitive/compulsive behaviors
          • disturbed states of anxiety
          • but not the hyperactivity of the mice tested
          • 5 mg attenuated the increased protein levels in the hippocampus and cerebellum of
            • NF-κB p65
            • COX-2
            • iNOS
          • Simultaneous administration of an HR agonist or an anticholinergic drug abolished the improvement in social parameters
    • ST-22234546
      • H3R/D2R/D3R receptor antagonist
      • 2.5, 5 and 10 mg/kg, i.p. significantly and dose-dependently attenuated social deficits and disturbed anxiety in BTBR mice
      • Increase of histamine in
        • Cerebellum
        • Striatum
      • Increase in dopamine in
        • PFC
        • Striatum
      • Increase in acetylcholine in
        • PFC
        • Striatum
        • Hippocampus

5.4. H4 histamine receptor

  • High histamine affinity1
  • Can be found at4
    • Immune cells
      • Mast cells
      • Eosinphils
      • Dendritic cells
    • Microglia (brain)
    • Not yet detected on neurons (presumably problem with detection methods)
  • Homology to H3R of approx. 40 %4
  • Signal paths:4
    • Gi/Go-coupled GPCRs
      • Reduces cAMP accumulation
    • Increases Ca2+ mobilization
    • Activates kinases (ERK, PI3K and MAPK)
    • Activates the transcription factor activating protein-1
  • Regulatory area
    • Mast cell chemotaxis
    • H4R stimulation increases histamine and cytokine production1
  • Agonists
    • Histamine
    • 4-Methylhistamine
    • Immepip47
  • Antagonists
    • Thioperamide
    • JNJ 7777120
      • Inhibits pro-inflammatory microglia and Parkinson’s development in rat model48

5.5. Histamine receptor heteromers

Receptor heteromers are receptor networks consisting of several receptors of different neurotransmitters.
Histamine receptors form heteromers, among other things, as:49
H3R/Dopamine D2R
H3R/Dopamine D1R
H3R/Adenosine A2A

6. Effect of histamine

Histamine is a potent mediator of many biological reactions

  • IgE-dependent release (allergic reaction)
    • Mast cell degranulation in allergies through cross-linking of IgE antibodies on the cell surface after binding of the allergen
  • IgE-independent release (allergy-independent)50
    • is regulated by the cyclic nucleotides cAMP and cGMP as “second messengers”
    • Histamine or b-adrenergic stimuli increase the cAMP concentration
      • cAMP inhibits the degranulation of mast cells
    • Histamine release is increased by
      • a-adrenergic and cholinergic influences
        • lowers cAMP
        • promotes histamine release
      • certain inflammatory cytokines
      • Binding of the complement factors C5a, C3a to receptors on mast cells
    • “Non-allergic” histamine liberators can be
      • Medication
      • Foodstuffs
      • chemical stimuli
      • physical stimuli
      • Hypoxia
      • Neuropeptides
      • Enzymes
        • Phospholipase
          Histamine influences
  • In the brain4
    • Arousal (arousal)
    • Awakening
    • Maintaining vigilance29
    • Learning and memory4
      • Histamine appears to play an important role in learning and memory via H1R and H2R
      • HDC-deficient mice show
        • specific changes in task-related learning and memory
        • improved performance in passive avoidance and fear memory
        • gender-specific deficiency or an improvement in the recognition of water labyrinths and new locations
      • Pharmacological blockade of H1R impairs
        • the spatial memory
        • the consolidation of object recognition memory
        • the avoidance memory
      • H2R antagonists block the consolidation of object recognition memory and inhibitory avoidance memory
      • Histamine improves both spatial working and reference memory functions through H1R and H2R in the radial maze task after scopolamine-induced memory deficits
      • H1R or H2R knockout mice show
        • Impairments in object recognition
        • Impairments in the acquisition of spatial memory
        • Improvements in auditory and contextual freezing
      • H1R knockout mice also show
        • severe impairment of memory for temporal sequences
        • Feeding
        • Energy
      • H3R antagonists
        • Show protective effect in various cognitive impairments in Y-maze, object recognition, passive avoidance, radial arm maze and water maze tests
        • Improved detection by the H3R antagonist ciproxifan appears to be at least partially dependent on H1R and H2R
        • Showed memory improvements in Alzheimer’s disease
  • Immune system51
    • Histamine stimulates recruitment of mast cells and basophils at the site of inflammation
      • Reaction to various stimuli such as allergens, pathogens and stress
    • In the innate immune system
      • Intensifies inflammatory reaction
      • Can promote the development of chronic inflammation, apparently via H1R
    • In the adaptive immune response
      • Histamine regulates adaptive immune responses at a systemic level (i.e. vascular system, respiratory tract, gut, microbiota, skin and nervous system)
  • The digestive system51
    • H2R antagonists have a gastroprotective effect
      • Gastritis
      • Gastroesophageal reflux
      • Prevention and treatment of peptic ulcers / bleeding when taking non-steroidal anti-inflammatory drugs (NSAIDs)
  • Social behavior
    • H3R antagonists showed improvements in autistic behaviors
  • Migraine
    • Histamine has a vasodilating effect
    • Migraine attacks are less frequent in the evening, correlating with lower central histaminergic arousal
    • Histamine is involved in migraine pathogenesis via inflammatory pathways
    • Plays a decisive role via an inflammatory pathway
      • H3R agonists are said to have anti-nociceptive and anti-neurogenic anti-inflammatory effects
  • Motivation and stress response52
    • Acute immobilization stress acts via histamine signaling at glutamatergic synapses of D1 receptor-expressing [D1(+)] medium spiny neurons (MSNs) in the nucleus accumbens nucleus
    • Histamine inhibits excitatory gain on D1(+) MSNs via presynaptic H3 receptor-dependent long-term depression, which requires Gβγ-driven Akt-GSK3β signaling
    • Histamine asymmetrically regulates glutamatergic transmission from the PFC and mediodorsal thalamus, with inputs from the PFC cortex undergoing robust long-term depression by histamine
    • Acute immobilization stress attenuates this long-term depression by recruiting endogenous H3 receptor signaling in the nucleus accumbens at glutamatergic synapses on D1(+) MSNs

7. Disorders of the histamine system

Dysfunctions are associated with neuropathological disorders, e.g.12

  • Narcolepsy

    • A significantly reduced brain histamine level was found in narcolepsy35
  • Hallucinations

  • Schizophrenia-like conditions
    An influence of histamine on schizophrenia itself has not yet been proven.53

  • Sleep problems

    • Histamine neurons4
      • Stop firing during the transition from wakefulness to sleep
      • Silence during slow-wave sleep and REM sleep
      • Start firing again after the transition to the waking state
      • Lowest firing in the awake idle state
      • Moderate firing during active wakefulness
      • Maximum firing with high vigilance
    • HDC knockout mice (impaired histamine synthesis) show
      • Sleep fragmentation
      • Increased REM sleep during the light period
      • Significant alertness deficits at the onset of darkness
    • H1 receptor antagonists can help with insomnia53
    • H1R antagonists promote sleep
    • Pathways of histamine on sleep:4
      • The ventrolateral preoptic nucleus (VLPO) is associated with the promotion of sleep
      • Histamine inhibits VLPO neurons indirectly by activating GABAergic interneurons, which in turn disinhibits histaminergic neurons to promote wakefulness
      • Histaminergic axons release paracrine GABA in the neocortex to prevent overactivation by histamine and regulate the level of alertness
      • Histamine can also directly modulate glutamatergic neurons of the thalamus and cause a general excitatory effect in several brain regions
      • Histamine triggers cortical activation through:
        • Activation of cholinergic neurons in the basal forebrain
        • Activation of cholinergic neurons in the mesopontine tegmentum
        • Activation of serotonergic neurons in the dorsal raphe nucleus
        • Direct projections into the cortex
      • The hypocretin system maintains wakefulness largely via histaminergic neurons
      • HCRT neurons and histaminergic neurons
        • Lie next to each other in the human hypothalamus
        • Overlap in their projections
        • HCRT neurons directly excite histaminergic neurons via the HCRT receptor 2
      • Histamine possibly regulates HCRT neurons via the H1R
        • The H1R antagonist pyrilamine inhibits HCRT-induced arousal in rats
        • H1R knockout mice show no HCRT-induced increase in alertness
  • Tourette (rare)

  • Alzheimer’s and Parkinson’s

    • High histamine levels in the substantia nigra correlate with a reduced number of dopaminergic cells
    • The H1 receptor appears to be affected53
  • Huntington

  • Depression

    • Reduced H1 receptor binding

7.1. Histamine deficiency

  • Tourette syndrome5455
    Histidine decarboxylase knockout (HDC-KO) mice exhibit stereotypic locomotor behaviors that reflect the core phenomenology of Tourette’s.56
  • Rare gene variants of the histamine receptor gene appear to be involved in Tourette’s and Autism Spectrum Disorders.5758

7.2. Histamine excess / histamine intolerance

7.2.1. Development of histamine intolerance

A very good German-language presentation on histamine intolerance can be found at59.

Histamine intolerance is based on an excess of histamine in relation to histamine breakdown.
Histamine obesity can have various causes:

  • Excessive histamine intake (food, fish poisoning)
  • Too little histamine breakdown
    • Mostly diamine oxidase deficiency (peripheral)
    • HNMT deficiency (CNS)
  • Smoking appears to increase histamine levels6061626364
    Histamine moderates reactions to cigarette smoke.65 However, reports that smoking reduces histamine levels66 or leaves them unchanged67 are the exception. However, it is conceivable that smoking increases the reaction to histamine.68697071
  • The cause may also be a systemic mast cell activation disease (MCAD)
    Pathologically altered mast cells (mastocytes, a type of immune cell used to defend against foreign bodies) produce histamine and other messenger substances (mediators). The incidence of MCAD is estimated to be between 1 and 17%.72
    Very good presentation of MCAD at https://www.mastzellaktivierung.info/73
    MCAD works primarily, but not only, by means of histamine.
    • Types of MCAD:
      • Mast cell activation syndrome (MCAS)
      • Systemic mastocytosis (SM) (rare)
      • Mast cell leukemia (MCL) (rare)
    • Mechanisms of action of an MCAD:74
      Percentages indicate the consensus that the mediators mentioned play a role in MCAD.
      • Histamine
        • Headache
        • Low blood pressure
        • Hives (red wheals, urticaria)
          • With or without angioedema (rapidly developing painless swelling)
        • Itching (pruritus)
        • Diarrhea
      • Prostaglandin-D2 (PGD2) (95 %)
        • Mucus secretion
        • Constricted airways (bronchoconstriction)
          • In interaction with thromboxane and PGF2α
        • Vascular instability (dilation of the blood vessels)
        • Sleep inducing
        • Lowering body temperature
        • Possible cause of hereditary hair loss in men together with the steroid hormone dihydrotestosterone (DHT)75
      • PAF2 (platelet-activating factor) (90 %)
        • Abdominal cramps
        • Pulmonary edema
        • Urticaria
        • Bronchoconstriction
        • Hypotension
        • Cardiac arrhythmia
      • Proinflammatory cytokines (80 %)
        • Local inflammation
        • Edema formation
        • Leukocyte migration 80 %
      • LTC4 and LTD4 (80 %)
        • Mucus secretion
        • Edema formation
        • Vascular instability
      • Chemokines (70 %)
        • Acute inflammation
        • Leukocyte recruitment
        • Leukocyte migration
      • Tryptase (65 %)
        • Endothelial activation with subsequent inflammatory reactions
      • Leukotrienes76
        • Allergic reactions
        • Inflammatory reactions

An excessive histamine level causes pseudoallergic symptoms. These vary greatly from person to person, making a diagnosis based on a list of symptoms very difficult.

7.2.2. Frequency of histamine intolerance

The prevalence is 1% of the population. 80% of people with ADHD are middle-aged women, 20% are men.50
More recent studies arrive at higher prevalence values.

7.2.3. Possible symptoms of histamine intolerance

  • Skin
    • Reddening of the skin
    • Hives
    • Eczema
    • Itching[7]
  • Head
    • Headache
    • Feeling of heat
    • Migraine
    • Dizziness
  • Airways
    • Narrowed or runny nose
    • Breathing difficulties
    • Bronchial asthma
    • Sore throat
  • Digestive system
    • Flatulence (bloating)
    • Diarrhea
    • Constipation
    • Nausea/vomiting
    • Abdominal pain
    • Stomach stitches
    • Heartburn
  • Cardiovascular system
    • Changes in blood pressure
      • High blood pressure (hypertension)
      • Low blood pressure (hypotension)
    • Palpitations (tachycardia)
    • Cardiac arrhythmia
  • Urology
    • Menstrual cramps (dysmenorrhea)
    • Cystitis
    • Urethritis
    • Irritation of the mucous membranes of the female genitals
  • Fabric
    • Water retention (edema)
    • Bone marrow edema (BME)
    • Joint pain
  • Energy balance
    • States of exhaustion
    • Seasickness
    • Tiredness
    • Sleep disorders
  • Mental symptoms
    • Confusion
    • Nervousness
    • Depressive moods

7.2.4. Foods that increase histamine

A list of histamine-increasing foods can be found at 77
There are various ways in which food can increase histamine levels.

7.2.4.1. Effects of the histamine increase
7.2.4.1.1. Containing histamine

Foods that contain histamine increase the histamine level.

7.2.4.1.2. Histamine liberators

Some foods cause an increased release of histamine from the salivary vesicles.

7.2.4.1.3. DAO inhibition

Certain substances inhibit the breakdown of histamine by diamine oxidase (DAO).

7.2.4.1.4. DAO mining competitors

Some foods contain substances that also require diamine oxidase (DAO) to break down histamine, which means that less DAO is available to break down histamine.

7.2.4.1.5. Increase in intestinal permeability for histamine

Substances that increase the permeability of the intestinal wall also increase the absorption of histamine.

7.2.4.2. List of triggers for histamine intolerance and MCAD

A very good compilation of MCAD triggers can be found at https://www.mastzellaktivierung.info/78

Foods with high histamine levels are listed in Quade, Bailly, Bartling, Bliesener, Springer: Histamine intolerance.79 This presentation only concerns foods with a high histamine content, not e.g. histamine liberators or DAO degradation competitors.

7.2.5. Treatment of histamine intolerance

The treatment of first choice is a low histamine diet.

A strict low-histamine diet for one month often helps to completely empty the histamine stores. After that, a limited consumption of individual histamine-increasing foods is usually possible. Smoking increases the histamine level considerably and thus undermines the histamine diet.61

In addition, the missing DAO enzyme can be taken 15 to 30 minutes before meals. Taking DAO can only compensate for individual “sins”, but cannot fundamentally avoid a diet.

8. Histamine and ADHD

There is barely any positive knowledge of a correlation between histamine intolerance and ADHD. NCBI / Pubmed did not find a single article under “histamine intolerance adhd”.80

A large cohort study found that taking antihistamines (especially first-generation antihistamines) in the first years of life significantly increased the risk of later ADHD. Disorder of REM sleep was cited as a possible cause, which secondarily impaired brain maturation.81
According to another study, former use of antihistamines in people with ADHD increased ADHD symptoms.82

Food additives (here: Sun yellow, carmoisine, tartrazine, ponceau 4R; quinoline yellow, allura red, sodium benzoate) can cause histamine release from circulating basophils. This is not allergic, i.e. not dependent on immunoglobulin E. The increased release of histamine can - in carriers of certain gene variants of the genes that encode histamine-degrading enzymes - increase ADHD symptoms83

A report of 4 individual cases of learning disabled children with ADHD described a very large improvement in ADHD symptoms with antihistamines.84

The H3 histamine receptor is thought to be involved in arousal, control of pituitary hormone release, cognitive function, motivation, goal-directed behavior, memory and sleep-wake cycles. However, clinical trials of H3 receptor drugs for ADHD (MK-0249, Bavisant, PF-03654746) have been unsuccessful in phase 2 trials or have been discontinued in phase 2 (betahistine).85

8.1. Histamine often elevated in ADHD

A case study reports an individual case in which methylphenidate caused chronic eosinophilic pneumonia. After discontinuation of MPH and resolution of the pneumonia, it recurred when MPH was taken again, together with reddening of the skin (rush).86 Rush can be a sign of histamine intolerance. Eosinophils are closely linked to the histamine system.

8.1.1. Histamine degradation by DAO often reduced in ADHD

A Spanish study found a genetically reduced diamine oxidase (DAO) activity in 82.1% of 40 children with ADHD and a greatly reduced DAO activity in 15.2% (i.e. reduced histamine degradation and consequently a (peripherally) increased histamine level).51 The study is to be extended to 200 children with ADHD and 100 controls. DAO is also called ABP1.

8.1.2. Histamine degradation often reduced by HNMT in ADHD

Furthermore, a correlation between ADHD and reduced histamine N-methyltransferase has been described, which also leads to reduced histamine degradation and increased histamine.11
Various HNMT gene polymorphisms are relevant in ADHD and other disorders:

  • Thr105Ile (rs11558538) showed83
    • reduced thermal stability
    • reduced activity of HNMT87, consequently less histamine degradation
    • more adverse effect of food additives on ADHD symptoms in 3- and 8/9-year-old children
    • a reduced risk of Parkinson’s disease88
  • T939C showed
    • more hyperactivity83
    • more adverse effect of food additives on ADHD symptoms in 3- and 8/9-year-old children83

Other gene variants and their influences on HNMT enzyme activity are known, but without reports of an ADHD correlation:

  • G179A showed
    • impaired HNMT enzyme activity
    • mental disability89
  • C314T showed
    • reduced HNMT enzyme activity
    • Km value for histamine increased 1.3-fold (= lower binding affinity)
    • Km value for SAM increased 1.8-fold (= lower binding affinity)
    • rather no correlation with asthma or rhinitis
  • T632C showed
    • impaired HNMT enzyme activity
    • mental disability89
  • A939G (also known as C939T/ rs1050891)83 shows
    • increased HNMT mRNA stability
    • increased HNMT enzyme activity90

8.2. Histamine and dopamine

Animal studies found a correlation between high histamine levels in the substantia nigra and a breakdown of dopaminergic cells, causing reduced dopamine levels.12 So far, no therapeutic benefit of H3 antagonists (which reduce histamine levels and increase dopamine levels) on Alzheimer’s or ADHD has been found.53

Receptor heteromers:4

  • H3R - D1R - Heteromers
    • D1R activation inhibits the production of cAMP instead of stimulating it as usual
    • H3R activation should reduce D13 affinity
  • H3R - D2R - Heteromers
    • only appear to reduce the dopamine affinity of the receptor

The histaminergic system appears to be closely linked to the dopaminergic system and synaptic transmission in the striatum (collection adapted from Hu, Chen (2017), unless another source is cited):4

  • Histaminergic neurons can also release dopamine (or GABA) as well
  • Over 85% of D1R- and D2R-expressing MSNs in the dorsal and ventral striatum contain H3R91
    • The synergistic effects of ciproxifan and halperidol suggest a direct, functional H3/D2 receptor interaction in striatopallidal neurons, so that H3R antagonists could be useful tools to improve the symptomatic treatment of schizophrenia
  • Histamine can selectively activate microglia, leading to increased inflammation characteristic of PD pathology, and damage dopaminergic neurons of the SNc
  • The H3R agonist Immepip alleviates apomorphine-induced turning behavior in 6-hydroxydopamine (6-OHDA)-lesioned rats
  • Simultaneous administration of Immepip or Imetit with L-DOPA alleviates L-DOPA-induced dyskinesia or chorea, but not dystonia
  • Intranigral injection of Immepip increases turning after systemic apomorphine administration in rats
  • The H3R antagonist thioperamide alleviates apomorphine-induced stereotypic behavior in rats with 6-OHDA lesions
  • The H3R antagonist pitolisant alleviates excessive daytime sleepiness in patients with Parkinson’s disease; motor performance remains unchanged.
  • Histamine H2R levels in the striatum are unchanged in patients with Parkinson’s disease. Nevertheless, the H2R antagonists famotidine and ranitidine enhance the antiparkinsonian effect of L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease in macaques and in the 6-OHDA model in rats. H2R antagonists could therefore serve as an aid in the treatment of Parkinson’s disease.
  • The TMN contains a group of dopaminergic neurons in the TMN that share electrophysiolgical properties with histaminergic neurons
  • H3Rs are expressed on GABAergic input terminals from the substantia nigra reticulata. Stimulation of these receptors reduces GABA release, resulting in increased excitation of dopaminergic cells in the substantia nigra pars compacta
  • Histamine inhibits dopamine release in the mouse striatum via H3R, unlike H3R antagonists
  • Histamine inhibits both cortical and thalamic excitatory projections to MSNs via presynaptic H3Rs
  • Histamine can selectively modulate the dynamics of thalamostriatal synapses to facilitate thalamic inputs
  • Histamine depolarizes both MSN classes via the effect of the H2R
  • Histamine suppresses lateral feedback inhibition between MSN through the H3R or H2R
  • The effect of H2R may be indirectly caused by the activation of H2R in cholinergic interneurons to increase acetylcholine release in the striatum
  • H3R agonists modulated in D2R-SPNs (but not in D1R-SPNs)91
    • Akt (serine/threonine PKB) glycogen synthase kinase 3 beta signaling in response to D2R activation via a β-arrestin 2 dependent mechanism
    • The phosphorylation of mitogen- and stress-activated protein kinase 1 and rpS6 (ribosomal protein S6) remained unchanged
  • The selective H3R agonist R-(-)-α-methylhistamine dihydrobromide attenuates movement activity and stereotypical behavior triggered by D2R agonists91
  • H1R and H2R are co-localized on D1R- and D2R-expressing MSNs and mediate histamine-induced excitation of the two neuron types92
  • Histamine excites dopamine D1R- and D2R-expressing neurons in the striatum equally strongly. This takes place via postsynaptic H1R and H2R.92
  • Genetic histamine deficiency causes upregulation of dopamine neurotransmission93
  • Increased histaminergic innervation of the entopeduncular nucleus (EPN) in a mouse model of Parkinson’s disease activates parvalbumin neurons (PV) of the EPN that project to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated channels (HCN) coupled to postsynaptic H2R. Presynaptic H3R activation in the glutamatergic neurons of the subthalamic nucleus (STN) projecting into the EPN inhibits this. Activation of both receptor types improves the motor dysfunction associated with parkinsonism. Pharmacologic activation of H2R such as genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, improves parkinsonism-associated motor dysfunction independent of changes in neuronal firing rate. Optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing firing rate rather than altering the firing pattern of EPNPV neurons94
  • In embryos, histamine appears to decrease dopaminergic gene transcription by altering several epigenetic components related to DNA and histone modifications, affecting the development of mDA neurons during development. Histamine showed a long-term effect on the formation of the nigrostriatal and mesolimbic/mesocortical pathways. Histamine caused:95
    • A significant decrease in TH immunoreactivity in the midbrain
    • Changes in dopaminergic neuronal fibers
    • A significantly smaller TH-positive area in the forebrain with whole-body staining
  • The H3R agonist α-methylhistamine decreased dopamine release in the ventral (but not in the dorsal) striatum by reducing the activity of striatal cholinergic interneurons96
  • HDC-KO mice lack the histamine-producing enzyme histidine decarboxylase (HDC) and therefore also histamine. HDC-KO mice showed:97
    • A pronounced pattern of behavior when exploring a new environment, in particular
    • An increased frequency of sitting up against the wall, jumping and head/body shaking.
    • Reduced dopamine and serotonin levels in the striatum
    • Increased DOPAC dopamine metabolite levels
    • Reduced gene expression of dynorphin and enkephalin
    • Increased striatal dopamine turnover after treatment with the dopamine precursor l-dopa
  • An H3R antagonist98
    • Attenuated the D1R-induced cell death signaling and neuronal degeneration that exists in Huntington’s disease
    • Reduced cognitive and motor learning deficits and loss of D1R-H3R heteromer expression in the Huntington’s disease mouse model
  • H3R antagonists (GT-233, 1 mg/kg s.c. and ciproxifan, 3 mg/kg s.c.) significantly and dose-dependently improved the learning performance of SHR pups, as did methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (agonist at nicotinic acetylcholine receptors, 0.03 mg/kg s.c.). The H3R agonist (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the cognition-enhancing effect of ciproxifan.99
  • H3R regulate the striatum100
  • An HNMT inhibitor reduced dopamine and histamine turnover in the striatum, nucleus accumbens and hypothalamus101
  • H3R are co-expressed with D1R by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses47
  • H3R-KO fish show reduced dopamine and serotonin levels102

8.3. Habenula, ADHD and histamine

Early childhood lesions of the habenula cause behavioral and brain changes similar to those seen in ADHD.103
Histamine H3 receptor antagonists eliminate these symptoms.104

The habenula

  • Transmits limbic information to the midbrain monoamine system
    • Is thereby involved in the regulation of monoamine release in target brain areas such as the striatum, where some of the biological substrates process time perception.
  • Is part of the circadian rhythm network and involved in sleep regulation

ADHD often shows changes in the circadian rhythm, sleep disorders and time perception.

8.4. Histamine in spontaneously hypertensive rat (SHR)

The SHR is the most widely used model animal for ADHD.
Compared to WKY, the SHR:105

  • Histamine
    • increased in
      - Hypothalamus (anterior and posterior) of young and adult SHR
      - Brain stem of young SHR
    • unchanged in
      • Cortex-midbrain
        • but higher in adult WKY and SHR than in young
    • reduced histamine metabolism in:106
      • Hypothalamus
      • Brain stem
      • Chronic L-histidine administration did not affect the hypertension of the SHR
        • different: Chronic administration of L-histidine (100 mg / kg twice daily for 4 weeks) to young SHR prevented the age-related increase in blood pressure and urine norepinephrine levels typical of SHR.107
    • increased histamine release from mast cells108109
      • with reduced nitric oxide release from mast cells108
  • Histidine decarboxylase activity
    • unchanged in
      • Posterior hypothalamus of young and adult SHR
      • Medulla oblongata of young and adult SHR
      • Hypothalamus anterior young SHR
      • Cortex-midbrain and in the brainstem of adult SHR (but higher than in young SHR and WKY)
    • slightly increased
      • Hypothalamus anterior adult SHR
    • increased
      • in the midbrain cortex of young and adult SHR
  • Histamine N-methyltransferase
    • increased
      • in the midbrain cortex of young SHR
    • reduced
      • in the cortex-midbrain of adult SHR
  • H3 receptor110
    • reduced number of amplificates
    • increasing H3 receptor density in the cortex with age as the number of expressed amplicons decreases
    • despite the decrease in the number of expressed amplicons of the H3 receptor, the expression of the larger amplicon (~500 bp) increased

Depletion of histamine in young SHR caused a delay in the age-typical rise in blood pressure.111
Chronic administration of L-histidine (100 mg / kg twice daily for 4 weeks) to young SHR prevented the age-related increase in blood pressure and urine norepinephrine levels typical of SHR.107
Histamine appears to lower blood pressure in SHR by attenuating sympathetic production via the central histamine H3 receptor. The antihypertensive effects of L-histidine correlated with an increase in nitric oxide in the rostral ventrolateral medulla.

H3R antagonists (GT-233, 1 mg/kg s.c. and ciproxifan, 3 mg/kg s.c.) (which have the effect of increasing histamine) significantly and dose-dependently improved the learning performance of SHR pups, as did methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (agonist at nicotinic acetylcholine receptors, 0.03 mg/kg s.c.). The H3R agonist (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the cognition-enhancing effects of ciproxifan.99

In SHR, the histamine doses that make the blood-brain barrier more permeable deviate upwards or downwards.112

8.5. Almost all ADHD medications increase histamine

All common ADHD medications increase histamine. MPH and AMP also increase the breakdown of histamine by DAO.
Only viloxazine does not appear to increase histamine.

More on this under Histamine intolerance / mast cell activation syndrome In the article Choice of medication for ADHD or ADHD with comorbidity


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