Histamine

Histamine is a biogenic amine and acts as a neurotransmitter and hormone. It could have a relevant significance in ADHD.
Histamine helps to regulate the release of dopamine. Almost all ADHD medications increase histamine. Histamine often appears to be elevated in ADHD.

The histamine system essentially consists of the histaminergic nerve cells in the tuberomammillary nucleus (TMN), which transmit to almost all brain regions and bind to 4 types of histamine receptors. Activated H1R and H2R have a histamine-increasing effect, while activated presynaptic H3R (autoreceptors) inhibit histamine, acetylcholine and dopamine¹
Histamine is strongly linked to the immune system. ADHD, like ASD, is associated with neuroinflammation, among other things.²

Histamine is toxic in high doses. Spoiled fish triggers histamine poisoning within 20 minutes.
Histamine is a strong inflammatory mediator with pleiotropic effects and is involved in the regulation of innate and adaptive immunity.³ ADHD, like ASD, is associated with neuroinflammation, among other things.²

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.

An intact histamine system is necessary for the antidepressant effect of SSRIs.⁴

• 1. Development of histamine
  • 1.1. Pathway of histamine formation
    • 1.2. Site of histamine formation in the brain
  • 1.3. Histamine in the body (peripheral)
  • 1.4. Histamine and the blood-brain barrier
• 2. Storage of histamine
• 3. Release of histamine
• 4. Breakdown / reuptake of histamine
  • 4.1. Dismantling
    • 4.1.1. Degradation in the brain (CNS) primarily due to HNMT
    • 4.1.2. Degradation in the body primarily by diamine oxidase (DAO, histaminase)
  • 4.2. Resumption
    • 4.2.1. Plasma membrane monoamine transporter (PMAT)
    • 4.2.2. Cation transporter 3, Organic cation transporter 3 (OCT3, SLC22A3)
    • 4.4.3. Cation transporter 2, Organic cation transporter 2 (OCT2, SLC22A2)
• 5. Histamine receptors
  • 5.1. H1 histamine receptor
  • 5.2. H2 histamine receptor
  • 5.3. H3 histamine receptor
  • 5.4. H4 histamine receptor
  • 5.5. Histamine receptor heteromers
• 6. Effect of histamine
• 7. What influences histamine
• 8. Disorders of the histamine system
  • 8.1. Histamine deficiency
  • 8.2. Histamine excess / histamine intolerance
    • 8.2.1. Development of histamine intolerance
    • 8.2.2. Frequency of histamine intolerance
    • 8.2.3. Possible symptoms of histamine intolerance
    • 8.2.4. Foods that increase histamine
      • 8.2.4.1. Effects of the histamine increase
        • 8.2.4.1.1. Containing histamine
        • 8.2.4.1.2. Histamine liberators
        • 8.2.4.1.3. DAO inhibition
        • 8.2.4.1.4. DAO mining competitors
        • 8.2.4.1.5. Increase in intestinal permeability for histamine
      • 8.2.4.2. List of triggers for histamine intolerance and MCAD
    • 8.2.5. Treatment of histamine intolerance
• 9. Histamine and ADHD
  • 9.1. Histamine often elevated in ADHD
    • 9.1.1. Histamine degradation by DAO often reduced in ADHD
    • 9.1.2. Histamine degradation often reduced by HNMT in ADHD
  • 9.2. Histamine and dopamine
  • 9.3. Habenula, ADHD and histamine
  • 9.4. Histamine in spontaneously hypertensive rat (SHR)
  • 9.5. Almost all ADHD medications increase histamine
  • 9.6. H2R deficiency can cause ADHD symptoms
  • 10. Histamine and stress

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.⁵

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.⁶ Synthesis of histamine and storage in vesicles of:⁷

• Tuberomammillary nucleus (TMN) in the posterior third of the hypothalamus
  • Neuronal histamine compartment²
    • Contains 60 to 80 % of the brain histamine
  • Main site of the histamine neurons
    • Human: 60,000 to 125,000 histaminergic neurons in the TMN²¹
    • Rats: 2,300¹⁸ to 4,600 histaminergic neurons (in the entire brain)
  • Send via axons to almost all brain regions², including in
    • Cerebral cortex⁷, mainly frontal, parietal and occipital lobes²
    • Cerebellum⁷²
    • Posterior pituitary gland⁷
    • Spinal cord⁷²
    • Hippocampus²
    • Amygdala²
    • VTA²
    • Nucleus accumbens²
    • Substantia nigra²
    • Middle thalamus region²
    • Striatum²
    • Medulla oblongata²
  • TMH cells produce GABA as well as histamine
  • 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 wakefulness⁹
  • 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.¹⁰
  • 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)¹¹, GABAergic¹²¹³ and noradrenergic cells (in the locus coeruleus).¹⁴
• Mastocytes (mast cells)
  • Mast cells permanently resident in the brain and mast cells crossing the BBB and traveling through the brain¹⁵
  • Contain considerable amounts of histamine from the brain (approx. 20 to 40 %)²
  • Are only found in
    • Thalamus
    • Hypothalamus
    • Dura mater
    • Leptomeninx
    • Choroid plexus
    • In the embryonic histamine system only in¹⁶
      • Pia
      • Brain parenchyma
• Microglia
• Microvascular endothelial cells

Histamine levels in the brain:²

• highest mirrors:
  • posterior hypothalamus: above 3.0 pmol/mg initial tissue = in the histaminergic neurons
  • anterior hypothalamus: over 1.5 pmol/mg
• mean levels in the whole brain
• lowest levels in cerebellum and medulla oblongata: approx. 0.12 pmol/mg

1.3. Histamine in the body (peripheral)¶

Synthesis of histamine and storage in vesicles peripherally in⁷

• 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 in³

• local immune reactions
• Digestive system

1.4. Histamine and the blood-brain barrier¶

While histamine cannot cross a healthy blood-brain barrier in adults, histamine is able to cross the blood-brain barrier during development.¹⁷

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 peripherally by

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

Release in the CNS must be distinguished from this.

4. Breakdown / reuptake of histamine¶

Histamine degradation takes place

• extracellular (esp. 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.¹⁸ Nτ-methylhistamine is oxidatively degraded via monoamine oxidases, diamine oxidases (extracellular) and aldehyde oxidases (intracellular) to Nτ-methylimidazolylacetic acid.¹⁹

HNMT is found in the human brain in neurons and glial cells in:¹⁸

• 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:¹⁸

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

People without a functioning HNMT show non-syndromic autosomal recessive intellectual disability.²⁰²¹

HNMT knockout mice showed:²²

• 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:¹⁸

• 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:¹⁸

• Histamine (Km: 19 µM in the intestine)²³
• 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.¹⁸
DAO is also expressed to a lesser extent in the kidneys, placenta²⁴ and lungs. DAO plays little to no role in the brain.²⁵
The optimum pH value for the breakdown of histamine by DAO is 6.4 to 6.6.²³
DAO dysfunctions appear to play a role in various diseases.

In the intestine:

• Histamine intolerance²⁶
• ischemic bowel syndrome²³
• Mesenteric infarction²³
• Ulcerative colitis²³

In the placenta²⁴

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

4.2. Resumption¶

Astrocytes and endothelial cells play an important role in histamine excretion.²⁷²⁸
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.²⁹
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.²⁹ PMAT and OCT 1 to 3 are therefore low-affinity “uptake 2” transporters.³⁰ 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 2004,³¹ 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.¹⁸
PMAT is significantly more involved in histamine reuptake than OCT3²⁸ in human astrocytes.²⁹
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.²⁹
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).³²
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.³³¹⁸

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.²⁹
Whether OCT3 reuptakes histamine not only in astrocytes but also presynaptically in histamine neurons remains to be seen.²⁹

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,²⁸ but in the human brain, as well as OCT1 (SLC22A1), OCTN1 (SLC22AN1) and OCTN2 (SLC22AN2).³⁴
The human OCT2 transports:²⁹

• 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 in²⁹
• Cortex
• Hippocampus
• Thalamus
• Hypothalamus
• dorsal raphe nucleus
• Locus coeruleus

Km for histamine:²⁹

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

5. Histamine receptors¶

5.1. H1 histamine receptor¶

• About as often as H2R⁷
  • Nevertheless functionally significant as H2R
• Postsynaptic²⁹
  • On non-neuronal target cells (like H2R, unlike H3R)²
• Low histamine affinity³
• Is expressed in various cells, including mast cells³
• Involved in type 1 hypersensitivity reactions³
• Coupled to⁷
  • Gq/11 protein¹
  • 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
  • Activated⁷
    • 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.⁶
    • Sleep³⁵
  • Vomiting
  • Bronchoconstriction
  • Neurotransmission
  • Possibly antidepressant
  • Possibly anticonvulsant
  • Possibly appetite suppressant
• Agonists
  • Histamine
  • Histaprodifen (selective agonist)
• Antagonists
  • All H1 antihistaminergics act as inverse agonists. The term antagonist is therefore misleading.³⁶
  • Loratadine
  • Cetirizine²
  • Fexofenadine
  • Doxylamine
  • Diphenhydramine²
  • Chlorpheniramine (antagonist / inverse agonist)³⁷²
  • Mepyramine²
  • Clemastine²
  • Pyrilamine²
  • Triploidin²

5.2. H2 histamine receptor¶

• About as often as H1R⁷
  • Nevertheless functionally less significant than H1R
• Postsynaptic²⁹
  • On non-neuronal target cells (like H1R, unlike H3R)²
• Low histamine affinity³
• Coupled to⁷
  Gαs¹
• Stimulates adenylyl cyclase⁷
  • 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 conductivity⁷
• Inhibits PLA2⁷
• Inhibits the release of arachidonic acid⁷
• Regulatory area
  • Aggression³⁸
  • Improvement of motor balance and motor coordination via H2 receptors in the cerebellum³⁹
  • Motor activity/exploratory behavior is increased via H2 receptors, not via H1 receptors⁵
  • Anxiety is primarily increased via H2R and only concomitantly via H1R⁵
  • Is mainly involved in the cytokine production of Th1 lymphocytes³
  • Gastric acid secretion
  • Reflex tachycardia
• Agonists
  • Histamine
  • Betazol
  • Amthamine²
  • Dimaprite²
  • Impromidine²
• Antagonists
  • Cimetidine
  • Famotidine
  • Ranitidine
  • Roxatidine
  • Nizatidine²

5.3. H3 histamine receptor¶

• High histamine affinity³
• Almost exclusively in the brain, only a few in the heart¹
  • Frequently in⁴⁰
    • Especially in dopamine-rich areas such as
      • Dorsal striatum
        • The vast majority of H3Rs are found postsynaptically in the dorsal striatum on the medium-sized spiny output neurons⁴¹⁴⁰
        • 95% (+/- 12%) of all D1-positive and 89% (+/- 12%) of all D2-positive cells in the striatum also contain H3R⁴²
      • Ventral striatum
      • Substantia nigra⁴³
      • Olfactory tubercles
      • But not
        • In the Calleja Islands
        • In VTA
    • PFC
    • Hippocampus
    • Amygdala
    • TMN
• Short (presynaptic)
  • Is found on histaminergic neurons (presynaptic autoreceptor, less common)⁷²⁹
    • On⁷
      • Soma
      • Dendrites
      • Axons
  • Not on all histaminergic neurons¹
    • Presynaptic = negative feedback to inhibit the synthesis and release of the neurotransmitter produced by the respective neuron
    • Apparently in TMN, Meynert nucleus (nucleus basalis magnocellularis) and cortex, but not in the dorsal and ventral striatum or nucleus accumbens⁴⁴⁴⁵
  • Also on terminals of non-histaminergic neurons presynaptically¹ (presynaptic heteroreceptor)²
  • In contrast, H1R and H2R are found on non-neuronal target cells² Therefore, only the H3R is relevant for the effect of histamine as a neurotransmitter
  • Other sources report H3R only as an autoreceptor²⁹
• Long (postsynaptic)
  • Most H3Rs are located postsynaptically on cells outside the neuronal histaminergic system²’
  • Can be found on
    • Other neurons, including glutamate, acetylcholine, GABA (heteroreceptor), large majority⁷²
    • On axons of other nerve cells² of the basal ganglia⁷
    • Is found particularly in the dorsal and ventral striatum
• H3R as well as HNMT, H1R and H2R appear to be frequently expressed in ASA.⁴⁶
• Signal paths:⁷
  • Primarily linked to Gi/o¹
    • Inhibits adenylyl cyclase and activates Ca2+ channels
    • Controls histamine synthesis and neurotransmitter release
    • Very high constitutive activity:³⁶
      • Gi/o protein is continuously activated, even if no histamine binds to the receptor
      • Even higher than for the other histamine receptors
      • This means that in addition to agonists and antagonists, there are also inverse agonists¹
  • Secondarily also involved in Gq/11 signaling¹
    • Activates PLA2
    • Activates Akt/glycogen synthase kinase-3 (GSK3)
    • Activates MAP kinase signaling pathways
  • 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
    • H3 antagonists increase the release of histamine (autoregulation) ⁵
    • H3R agonists
      • Inhibit acetylcholine²
      • Inhibit noradrenaline²
      • Inhibit serotonin²
      • Inhibit dopamine²
    • Glutamate
  • Regulation of the circadian rhythm
  • Involved in the function of the blood-brain barrier³
• Agonists
  • Histamine
  • Α-Methylhistamine²
  • Immepip²
  • Imetit²
• Antagonists / inverse agonists
  • Increase the activity of histaminergic neurons in the brain and thus promote arousal and cognition⁴⁷
  • Probably increase dopamine in the frontal cortex, while agonists decrease dopamine, at least in combination with dopaminergic drugs¹
  • Ciproxifan
  • Thioperamide
    • Parkinson’s disease⁴⁸
    • Increases motor activity / exploratory behavior⁵
    • Increases anxiety⁵
  • Pitolisant (antagonist/inverse agonist); Wakix® (pitolisanth hydrochloride)⁴⁸, selective H3R antagonist/inverse agonist⁴⁹
    • Narcolepsy, sleep disorders
      • A significantly reduced histamine level in the brain was found in narcolepsy⁵⁰
    • No effects on:⁴⁹
      • Striatal dopamine
        • Other than AMP, Modafinil, Solriamfetol
      • Locomotion
        • Even attenuated hyperlocomotion triggered by modafinil or solriamfetol
      • Food intake
  • H3RA 2-18⁴⁸
    • Epilepsy
  • Clobenpropit (antagonist, inverse agonist)
    • Apparently directly inhibited dopamine reuptake in vitro, as well as somewhat weaker norepinephrine reuptake in striatal and cerebro-cortical synaptosomes⁵¹
  • Iodophenpropit
    • Apparently directly inhibited dopamine reuptake in vitro, as well as somewhat weaker norepinephrine reuptake⁵¹
  • ABT-288 (selective H3R antagonist)⁵²
  • ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] (selective H3R antagonist)⁵³⁵⁴
    • 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
    • High affinity for rat H3R (pK(i) = 8.9) and human H3R (pK(i) = 9.5)
  • A-349821 (((4’-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone))⁵⁵
  • A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone]⁵⁶
    • 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)⁵⁷
    • social memory in the adult rat significantly improved by 3 and 10 mg/kg⁵⁷
  • A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide]⁵⁶
    • 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)⁵⁷
    • significantly improved social memory in the adult rat at 1 and 3 mg/kg⁵⁷
  • GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg)⁵⁷
  • Enerisant (competitive antagonist, inverse agonist)⁴⁷
    • [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.⁵⁸⁵⁹
      • 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-2223⁶⁰⁶¹
    • 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 affinity³
• Is mainly found in¹
  • Blood
  • Spleen
  • Lung
  • Liver
  • Intestine⁶²
  • CNS⁶³
• On non-neuronal cells⁷
  • Immune cells
    • Mast cells
    • Eosinophils
    • Dendritic cells
  • Microglia (brain)
  • Macrophages²
  • T lymphocytes²
  • Not yet detected on neurons (presumably problem with detection methods)
• Homology to H3R of approx. 40 %⁷
• Signal paths:⁷
  • Gi/Go-coupled GPCRs
    • Reduces cAMP accumulation
    • Reduces adenylate cyclase activity¹
  • Increases Ca2+ mobilization
  • Activates kinases (ERK, PI3K and MAPK)
  • Activates the transcription factor activating protein-1
• Regulatory area
  • Mast cell chemotaxis
  • Inflammations⁶⁴
    • H4R stimulation increases histamine and cytokine production³
  • Pain⁶⁵⁶⁶⁶⁷
• Agonists
  • Histamine
  • 4-Methylhistamine
  • Immepip⁶⁸
  • Clobenopropite (partial agonist)²
  • Clozapine³⁶
• Antagonists
  • Thioperamide²
  • JNJ-7777120
    • Inhibits proinflammatory microglia and Parkinson’s development in rat model⁶⁹²
  • 2-aminopyrimidines²
  • VUF-6002²
  • JNJ-10191584²
  • Toreforant (JNJ-38518168)²
  • CZC-13788²
  • PF-2988403²
  • A-940894²
  • A-987306²
  • JNJ-39220675⁷⁰

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:⁷¹
H3R/Dopamine D2R
H3R/Dopamine D1R
H3R/Adenosine A2A

While D1R are normally coupled to adenylate cyclase via Gs protein, this changes to Gi/o coupling when the D1 dimer dimerizes with the H3 receptor.⁷²
While H3R and D1R act alone against each other, because D1R is coupled to a Gs protein and H3R to a Gi/o protein, they act synchronously as heteromers like H3R. While dopamine normally enhances the activity of the direct pathway via D1R, it inhibits those cells of the direct pathway that are equipped with the D1-H3 heterodimer. This increases the imbalance between the direct pathway (which promotes movement) and the indirect pathway (which inhibits movement). Although these heterodimers have been shown to exist in vivo (Moreno et al., 2011), it is currently unknown how widespread they are and to what extent they contribute to the overall effect of dopamine in the dorsal striatum.

6. Effect of histamine¶

Histamine is a potent mediator of many biological reactions, especially inflammatory processes
Histamine is involved in the immune response to foreign pathogens and is produced by basophils and mast cells in the connective tissue around the pathogen.²

• IgE-dependent release (allergic reaction)
  • after binding of the allergen on the cell surface, histamine is released from the secretory granules of mast cells by cross-linking of IgE antibodies
• IgE-independent release (allergy-independent)⁷³
  • 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

One of the effects of histamine is²

• increased permeability of the capillaries. This enables white blood cells and some proteins (e.g. glycoproteins such as immunoglobulins) to penetrate infected tissue in order to fight the pathogens there.
• Itching as a result of direct stimulation of sensory (pain) nerve endings
• Activation and migration of endothelial cells, which is essential for angiogenesis.

The human intestinal microbiota can also produce histamine.²

Effect of histamine

• In the brain⁷
  • Arousal (arousal)
  • Awakening
    • Activation of TMN neurons promotes alertness
    • During non-REM (Nonrapid Eye Movement) sleep, TMNs fire very little
    • TMN are inactive during REM (Rapid Eye Movement) sleep
  • Maintaining vigilance³⁵
  • Learning and memory⁷⁷⁴⁶
    • 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
    • Formation or recall of memories requires a certain level of tonic TMN activity.
      • It is possible that strengthening histaminergic signaling in the brain could promote the recovery of seemingly lost memories⁷⁵
    • 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 system⁷⁶
  • 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
  • Adaptive immune response
    • Histamine regulates adaptive immune responses at a systemic level (i.e. vascular system, respiratory tract, gut, microbiota, skin and nervous system)
  • Neuroinflammation: depending on the cytokine profile, histamine can have a local proinflammatory or anti-inflammatory effect, also depending on the developmental stage of the CNS²
• The digestive system⁷⁶
  • 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 response⁷⁷
  • Acute immobilization stress acts via histamine signaling at glutamatergic synapses of D1 receptor-expressing [D1(+)] medium spiny neurons (MSNs) in the nucleus accumbens core
  • 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

Histamine can further influence

• Learning and memory processes⁷⁸
• Thermoregulation⁷⁸
• Satiety (due to histamine in the brain)⁷⁹
• Energy consumption is increased by histamine in the hypothalamus⁷⁸
• Glucose uptake and insulin function in the body⁷⁸
• Feeding behavior is reduced by histamine in the hypothalamus⁷⁸, while histamine generally increases arousal for feeding⁷⁹
• Improvement of motor balance and motor coordination via H2 receptors in the cerebellum³⁹
• Increases motor activity/exploratory behavior via H2 receptors, not via H1 receptors⁵
• Increases anxiety primarily via H2 receptors and concomitantly via H1 receptors⁵

7. What influences histamine¶

The release of histamine in brain neurons is increased by²

• Stimulation of N-methyl-D-aspartate or N-methyl-D-aspartate (NMDA) receptors
• Stimulation of μ-opioid receptors
• Stimulation of dopamine D2 receptors
• Stimulation of some serotonin receptors.

8. Disorders of the histamine system¶

Dysfunctions are associated with neuropathological disorders, e.g.¹⁹

• Narcolepsy
  • A significantly reduced brain histamine level was found in narcolepsy⁵⁰
• Hallucinations
• Schizophrenia-like conditions
  An influence of histamine on schizophrenia itself has not yet been proven.⁸⁰
• Sleep problems
  • Histamine neurons⁷
    • 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 insomnia⁸⁰
  • H1R antagonists promote sleep
  • Pathways of histamine on sleep:⁷
    • 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 side by side 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’s (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 affected⁸⁰
• Huntington
• Depression
  • Reduced H1 receptor binding

8.1. Histamine deficiency¶

• Tourette syndrome⁸¹⁸²
  Histidine decarboxylase knockout (HDC-KO) mice exhibit stereotypic locomotor behaviors that reflect the core phenomenology of Tourette’s.⁸³
• Rare gene variants of the histamine receptor gene appear to be involved in Tourette’s and Autism Spectrum Disorders.⁸⁴⁸⁵
• A histamine H2 receptor deficiency on parvalbumin-positive neurons in the substantia nigra pars recticulata⁸⁶
  • Weakens the neuronal activity of these neurons
  • Causes hyperactivity, impulsivity and inattention in mice
  • People with ADHD and mice with DAT deficits showed reduced H2R expression on parvalbumin-positive neurons in the substantia nigra pars recticulata
    • H2R agonists improved their ADHD symptoms

8.2. Histamine excess / histamine intolerance¶

8.2.1. Development of histamine intolerance¶

A very good German-language presentation on histamine intolerance can be found at⁸⁷.

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 levels^8889909192
  Histamine moderates reactions to cigarette smoke.⁹³ However, reports that smoking reduces histamine levels⁹⁴ or leaves them unchanged⁹⁵ are the exception. However, it is conceivable that smoking increases the reaction to histamine.^96979899
• 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%.¹⁰⁰
  Very good presentation of MCAD at https://www.mastzellaktivierung.info/¹⁰¹
  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:¹⁰²
    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)¹⁰³
    • 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
    • Leukotrienes¹⁰⁴
      • 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.

8.2.2. Frequency of histamine intolerance¶

The prevalence is 1% of the population. 80% of people with ADHD are middle-aged women, 20% are men.⁷³
More recent studies arrive at higher prevalence values.

8.2.3. 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

8.2.4. Foods that increase histamine¶

A list of histamine-increasing foods can be found at ¹⁰⁵
There are various ways in which food can increase histamine levels.

8.2.4.1. Effects of the histamine increase¶

8.2.4.1.1. Containing histamine¶

Foods that contain histamine increase the histamine level.

8.2.4.1.2. Histamine liberators¶

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

8.2.4.1.3. DAO inhibition¶

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

8.2.4.1.4. 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.

8.2.4.1.5. Increase in intestinal permeability for histamine¶

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

8.2.4.2. List of triggers for histamine intolerance and MCAD¶

A very good compilation of MCAD triggers can be found at https://www.mastzellaktivierung.info/¹⁰⁶

Foods with high histamine levels are listed in Quade, Bailly, Bartling, Bliesener, Springer: Histamine intolerance.¹⁰⁷ This presentation only concerns foods with a high histamine content, not e.g. histamine liberators or DAO degradation competitors.

8.2.5. 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.⁸⁹

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.

9. 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”.¹⁰⁸

Taking antihistamines (especially first-generation H1R antihistamines) in the first years of life appears to significantly increase the risk of later ADHD. Disorder of REM sleep, which secondarily impairs brain maturation, was cited as a possible cause.^109110111
According to another study, former use of antihistamines in people with ADHD increased ADHD symptoms.¹¹²

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 symptoms¹¹³

A report of 4 individual cases of learning disabled children with ADHD described a very large improvement in ADHD symptoms with antihistamines.¹¹⁴

The H3 histamine receptor is thought to be involved in arousal, control of pituitary hormone secretion, 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).¹¹⁵

9.1. 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).¹¹⁶ Rush can be a sign of histamine intolerance. Eosinophils are closely linked to the histamine system.
30% of children with ADHD showed elevated histamine urine levels. However, histamine levels did not correlate with the severity of ADHD symptoms.¹¹⁷

A histamine deficiency could also contribute to a dysregulation of the dopamine system.¹¹⁸

9.1.1. Histamine degradation by DAO often reduced in ADHD¶

A Spanish study found genetically reduced diamine oxidase (DAO) activity in 82.1% of 40 children with ADHD and severely reduced DAO activity in 15.2% (i.e. reduced histamine degradation and consequently (peripherally) increased histamine levels).⁷⁶ The study is to be extended to 200 children with ADHD and 100 controls. DAO is also called ABP1.
Among 303 children with ADHD, 78.8% were found to have at least one reduced active DAO allele. The severity of ADHD was not influenced by DAO. Certain DAO gene variants had a negative effect on working memory and a partly negative and partly positive effect on IQ.¹¹⁹

9.1.2. 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.¹⁸
Various HNMT gene polymorphisms are relevant in ADHD and other disorders:

• Thr105Ile (rs11558538) showed¹¹³
  • reduced thermal stability
  • reduced activity of HNMT¹²⁰, 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 disease¹²¹
• T939C showed
  • more hyperactivity¹¹³
  • more adverse effect of food additives on ADHD symptoms in 3- and 8/9-year-old children¹¹³

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 disability²⁰
• 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 disability²⁰
• A939G (also known as C939T/ rs1050891)¹¹³ shows
  • increased HNMT mRNA stability
  • increased HNMT enzyme activity¹²²

9.2. 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.¹⁹ So far, no therapeutic benefit of H3 antagonists (which reduce histamine levels and increase dopamine levels) on Alzheimer’s or ADHD has been found.⁸⁰

Receptor heteromers:⁷

• 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):⁷

• H3 antagonists/inverse agonists increase the release of dopamine
  • In the frontal cortex⁵³ in the presence of dopaminergic drugs or medications¹ and ACC¹²³
  • But not in the dorsal or ventral striatum (unchanged there)^{5344 1} or nucleus accumbens^12412570
  • But increased the release of dopamine to methamphetamine in the nucleus accumbens¹²⁵¹²⁶
  • H3R appear in the striatum¹
    • enhance the inhibition of the indirect pathway induced by dopamine (D2R) (as both are coupled to a Gi/o protein)
      • H3R agonists such as D2R agonists reduce GABA in the striatum, while
    • inhibit the excitation of the direct pathway induced by dopamine (D1R) (since D1R is coupled to a Gs protein and H3R to a Gi/o protein)
      • D1R agonists amplify GABA
      • H3R agonists inhibited D1R agonists¹²⁷ possibly via postsynaptic effect¹
• Histaminergic neurons can also release dopamine (or GABA) as well
  • 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 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
• H3R regulate the striatum¹²⁸
• Most H3Rs in the dorsal and ventral striatum are found postsynaptically on medium-sized spiny output neurons. These cells also contain a large number of D1R and D2R. H3Rs form receptor heterodimers with D1Rs and D2Rs.¹
• Over 85% of D1R- and D2R-expressing MSNs in the dorsal and ventral striatum contain H3R¹²⁹
• 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.¹³⁰
• An H3R antagonist¹³¹
  • 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
• Histamine excites dopamine D1R- and D2R-expressing neurons in the striatum equally strongly. This takes place via postsynaptic H1R and H2R.¹³²
• The H3R agonist α-methylhistamine decreased dopamine release in the ventral (but not in the dorsal) striatum by reducing the activity of striatal cholinergic interneurons¹³³
• H3R are co-expressed with D1R by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses⁶⁸
• H3R agonists modulated in D2R-SPNs (but not in D1R-SPNs)¹²⁹
  • 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 agonists¹²⁹
• H3R-KO fish show reduced dopamine and serotonin levels¹³⁴
• 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
• H1R and H2R are co-localized on D1R- and D2R-expressing MSNs and mediate histamine-induced excitation of the two neuron types¹³²
• Genetic histamine deficiency causes upregulation of dopamine neurotransmission¹³⁵
• 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 neurons¹³⁶
• 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:¹³⁷
  • 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
• HDC-KO mice lack the histamine-producing enzyme histidine decarboxylase (HDC) and therefore also histamine. HDC-KO mice showed:¹³⁸
  • 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 HNMT inhibitor reduced dopamine and histamine turnover in the striatum, nucleus accumbens and hypothalamus¹³⁹
• Dopamine modulation of the basal ganglia appears to be sex-specific:¹¹⁸
  • Histamine in the ventricles of the brain (intracerebroventricular) caused
    • Reduced dopamine in the striatum in male mice
      • Effect was dependent on H2R in the substantia nigra pars compacta (SNc)
      • Knockdown of H2R in GABAergic SNc neurons abolished the effect on
    • Increased dopamine in the striatum in female mice
      • H2R does not influence the effect of histamine on dopamine
      • H3R agonists in the striatum increased dopamine levels in the striatum
      • Effect of histamine on dopamine was modulated by the estrus cycle in females occurred only in proestrus, when estrogen levels are high, and in estrus

9.3. Habenula, ADHD and histamine¶

Early childhood lesions of the habenula cause behavioral and brain changes similar to those seen in ADHD.¹⁴⁰
Histamine H3 receptor antagonists eliminate these symptoms.¹⁴¹

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.

9.4. Histamine in spontaneously hypertensive rat (SHR)¶

The SHR is the most widely used model animal for ADHD.
Compared to WKY, the SHR:¹⁴²

• 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:¹⁴³
    • 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.¹⁴⁴
  • increased histamine release from mast cells¹⁴⁵¹⁴⁶
    • with reduced nitric oxide release from mast cells¹⁴⁵
• 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 receptor¹⁴⁷
  • 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.¹⁴⁸
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.¹⁴⁴
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.¹³⁰

In SHR, the histamine doses that make the blood-brain barrier more permeable deviate upwards or downwards.¹⁴⁹

9.5. Almost all ADHD medications increase histamine¶

All common ADHD medications increase histamine.¹⁵⁰
AMP (lisdexamfetamine) also increased histamine degradation by DAO by strongly upregulating DAO.¹⁵¹
Chronic administration of psychostimulants increases the release of histamine in the striatum.¹⁵²

Only viloxazine does not appear to increase histamine and has little effect on the histamine system¹⁵³

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

We consider:
Since hypothalamic neuronal histamine (as well as glucagon-like peptide-1 (GLP-1), corticotropin-releasing hormone (CRH)) suppresses food intake¹⁵⁴, the histamine increase mediated by ADHD medications, if it also occurs in the hypothalamus, could be a pathway mediating the known effect of appetite reduction by stimulants.

9.6. H2R deficiency can cause ADHD symptoms¶

A histamine H2 receptor deficiency on parvalbumin-positive neurons in the substantia nigra pars recticulata⁸⁶

• Weakens the neuronal activity of these neurons
• Causes hyperactivity, impulsivity and inattention in mice
• People with ADHD and mice with DAT deficits showed reduced H2R expression on parvalbumin-positive neurons in the substantia nigra pars recticulata
  • H2R agonists improved their ADHD symptoms

10. Histamine and stress¶

Histamine is involved in the regulation of the HPA stress axis in stressful situations ¹⁵⁵³⁶
Histamine release is a sensitive stress indicator. Immobilization stress and cold reduce histamine¹⁵⁶ or histamine turnover.¹⁵⁷ Short-term stress (5 minutes) reduces histamine in the midbrain, whereas prolonged stress (30 to 60 minutes) or repeated stress (15 minutes each) does not.¹⁵⁸ Exposure of rats to air blasts for 1, 5 and 15 minutes increased histamine in the hypothalamus. The histamine content in the midbrain was increased after 1 and 5 minutes of exposure, while the histamine level in the cerebral cortex only increased after 1 minute of exposure. Prolonged stress (30 minutes) did not affect histamine concentrations in the three brain regions studied, although plasma corticosterone levels remained very significantly (14.5-fold) elevated. Repeated exposure of rats to air bursts lasting 15 minutes led to a significant increase in histamine concentration in the hypothalamus, while histamine in the midbrain and cerebral cortex was not significantly altered.¹⁵⁹
In awake rats (12 months), 15 minutes of stress increased histamine in the hypothalamus, but not in the cortex or midbrain.¹⁶⁰
Acute stress increased histamine turnover in the diencephalon, nucleus accumbens and striatum. Chronic immobilization stress increased histamine turnover in the nucleus accumbens and the striatum, but not in the diencephalon¹⁵²
Rats have five different groups of histamine neurons (E1-E5) in the tuberomammillary nucleus (TMN) in the posterior hypothalamus. Immobilization stress, insulin-induced hypoglycemia and foot shock particularly activated the histamine-synthesizing neurons in E4 and E5. Up to 36% of HDC mRNA-expressing cells show c-Fos immunoreactivity in the E5 region. Immobilization stress also activated some neurons of the histaminergic groups E1, E2 and E3. Ether stress, acute hyperosmotic stimulation or the injection of bacterial lipopolysaccharide did not activate the hypothalamic histamine neurons¹⁵⁵

TMN neurons can integrate various stress signals (endocrine signals, external stimuli, body perception).¹⁵⁴
Stress triggers the neuroendocrine release of ACTH, beta-endorphin and AVP from the pituitary gland via histamine.¹⁶¹

Central administration of CRH increased histamine turnover. CRH-1 receptors are found on the cell body of histamine neurons.¹⁵⁴

Histamine injections into the PVN activate the HPA axis via CRH release. During systemic stress, mast cells in the leptomeninges and along the brain capillaries release histamine and CRH
and regulate the permeability of the blood-brain barrier in response to stress.¹⁶²