Histamine

Histamine is a biogenic amine that acts as both a neurotransmitter and a hormone. It may play a significant role in ADHD.
Histamine helps regulate dopamine release. Almost all ADHD medications increase histamine levels. In ADHD, histamine levels often appear to be elevated.

The histamine system consists primarily of histaminergic neurons in the tuberomammillary nucleus (TMN), which project to nearly all regions of the brain and bind to four types of histamine receptors there. Activated H1R and H2R receptors increase histamine levels, while activated presynaptic H3R (autoreceptors) inhibit histamine, acetylcholine, and dopamine.¹
Histamine is closely linked to the immune system. ADHD, like ASD, is associated with neuroinflammation, among other things.²

Histamine is toxic in high doses. Spoiled fish can cause histamine poisoning within 20 minutes.
Histamine is a potent inflammatory mediator with pleiotropic effects that plays a role in regulating innate and adaptive immunity.³ ADHD, like ASD, is associated with neuroinflammation, among other factors.²

H3 antagonists, which increase histamine levels, have a beneficial effect on various ADHD symptoms as well as on social symptoms associated with ASD. ADHD and ASD very often occur together. In addition, histamine may play a role in the disorders of the day-night rhythm that are common in ADHD.

A healthy histamine system is necessary for the antidepressant effects of SSRIs.⁴

1. Formation of Histamine¶

1.1. How Histamine Is Formed¶

Conversion of the amino acid L-histidine to histamine through

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

α-Fluoromethyl-histidine inhibits histamine synthesis.⁵

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

1.2. Where histamine is produced in the brain¶

Only a few nerve cells in the brain produce histamine.⁶ Synthesis of histamine and its storage in vesicles by:⁷

• Tuberomammillary nucleus (TMN) in the posterior third of the hypothalamus
  • Neural histamine compartment²
    • contains 60 to 80 percent of the histamine in the brain
  • Main site of histamine neurons
    • Humans: 60,000 to 125,000 histaminergic neurons in the TMN²¹
    • Rats: 2,300¹⁸ to 4,600 histaminergic neurons (in the entire brain)
  • Transmission via axons to nearly all regions of the brain², including
    • Cerebral cortex⁷, primarily the frontal, parietal, and occipital lobes²
    • Cerebellum⁷²
    • Posterior wall of the pituitary gland⁷
    • Spinal cord⁷²
    • Hippocampus²
    • Amygdala²
    • VTA²
    • Nucleus accumbens²
    • Substantia nigra²
    • middle thalamic region²
    • Striatum²
    • Medulla oblongata²
  • In addition to histamine, TMH cells also produce GABA
  • play a key role in regulating arousal and alertness
  • There appear to be 5 groups of TMN cells that differ, among other things, in their expression of the H3 receptor and in their co-release of GABA
  • Inactivation of the TMN by the GABA agonist muscimol results in 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 during quiet wakefulness, moderate during active wakefulness, and highest during attentive wakefulness.¹⁰
  • Histamine maintains wakefulness through direct projections from TMN cells to the thalamus and cortex, and indirectly through the activation of cholinergic (via H1 and H2 receptors)¹¹, GABAergic¹²¹³ , and noradrenergic cells (in the locus coeruleus).¹⁴
• Mast cells
  • mast cells that are permanently located in the brain, as well as mast cells that cross the blood-brain barrier and travel through the brain¹⁵
  • contain significant amounts of histamine from the brain (approximately 20 to 40%)²
  • are found only in
    • Thalamus
    • Hypothalamus
    • Dura mater
    • Leptomeningea
    • Choroidal plexus
    • in the embryonic histamine system, only in¹⁶
      • Pia
      • Brain parenchyma
• Microglia
• microvascular endothelial cells

Histamine levels in the brain:²

• Highest levels:
  • Posterior hypothalamus: greater than 3.0 pmol/mg of starting tissue = in the histaminergic neurons
  • Anterior hypothalamus: over 1.5 pmol/mg
• average values throughout the brain
• Lowest levels in the cerebellum and medulla oblongata: approximately 0.12 pmol/mg

1.3. Histamine in the Body (Peripheral)¶

Synthesis of histamine and its storage in vesicles in peripheral⁷

• Mast cells
• Basophils (basophilic granulocytes, a small subgroup of white blood cells (leukocytes))
• Epidermal cells
• Gastric mucosa
  • enterochromaffin-like cells, which regulate the release of stomach acid

Peripheral histamine is primarily involved in³

• local immune responses
• 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 via peripheral

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

This must be distinguished from release into the CNS.

4. Breakdown / Resynthesis of Histamine¶

Histamine is broken down

• extracellular (especially dietary histamine)
  • to imidazolylacetic acid via diamine oxidases (DOA, extracellular; formerly known as histaminase) and aldehyde oxidases (intracellular).
  • After ribosylation, excretion occurs via the kidneys.
• intracellular (e.g., in the liver)
  • through histamine methylation (ring methylation by histamine N-methyltransferase)
  • Plays only a minor role in histamine breakdown
  • In cases of HNMT deficiency, DAO-mediated breakdown may increase.

4.1. Mining¶

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 form inactive Nτ-methylhistamine.
HNMT (EC 2.1.1.8) catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to histamine, producing N-N-methylhistamine and S-adenosyl-L-homocysteine.¹⁸ Nτ-methylhistamine is oxidatively degraded by monoamine oxidases, diamine oxidases (extracellular), and aldehyde oxidases (intracellular) to form Nτ-methylimidazolylacetic acid.¹⁹

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

• Cerebellum (high levels)
• frontal cortices (moderate amount)
• parietal cortex
  • Hippocampus (moderate amount)
  • Caudate nucleus (moderate amount)
• temporal cortex
• occipital cortex

In humans, HNMT exhibits binding affinity for:¹⁸

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

People without functional HNMT exhibit non-syndromic autosomal recessive intellectual disability.²⁰²¹

HNMT knockout mice showed:²²

• drastically elevated histamine levels in the brain, both intracellular and extracellular
• other monoamines in the brain remain unchanged
• high aggressiveness due to excessive H2R activation
• reduced physical activity in home cages
  • presumably due to a disrupted sleep-wake cycle caused by excessive H1R activation
• no fear-like behaviors
• no depression-like behaviors
• no memory problems
• no motor impairments

HNMT inhibitors:¹⁸

• Metoprin
  • Capable of crossing the blood-brain barrier
  • Antinociception
  • Suppression of energy intake
  • hyperglycemic effect
  • Improvement in cognitive function
  • antiepileptic effect
  • Reduction of methamphetamine-induced behavioral abnormalities
  • Inhibition of dihydrofolate reductase
  • A reduction in cellular folate metabolism, which inhibits cell growth
• SKF91488
  • has difficulty crossing the blood-brain barrier
• Amodiaquine
• Chloroquine
• Dimaprit
• Etoprine
• Quinacrine
• Tacrine

4.1.2. Breakdown in the body occurs primarily through diamine oxidase (DAO, histaminase)¶

Diamine oxidase (DAO, also known as histaminase) is a homodimeric protein encoded by the AOC1 gene. DAO is found primarily in the microvilli of enterocytes.
DAO oxidatively deaminates various amines, including:¹⁸

• Histamine (Km: 19 µM in the intestine)²³
• Cadaverine (1,5-diaminopentane)
• Putrescine (IC₅₀: 83 µM)
• N-Tau-methylhistamine (N-methylhistamine, 1-methylhistamine) (Km: 97 µM)
• Spermidine
• Benzylamine (trace amounts)
• Methylamine (trace amounts).
  (Km: Michaelis constant; substrate concentration at which the reaction rate reaches half its maximum)

DAO is primarily expressed in the digestive tract, where it detoxifies histamine from food to reduce histamine uptake by enterocytes. If DAO function is impaired, this results in increased histamine uptake and, consequently, elevated blood histamine levels.¹⁸
In addition, DAO is expressed to a lesser extent in the kidneys, placenta²⁴, and lungs. In the brain, DAO plays little to no role.²⁵
The optimal pH level for DAO to break down histamine is 6.4 to 6.6.²³
DAO malfunctions appear to play a role in various diseases.

In the intestines:

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

In the placenta:²⁴

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

4.2. Resumption¶

Astrocytes and endothelial cells play an important role in histamine release.²⁷²⁸
The plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3) transport histamine in humans primarily into astrocytes, where it is metabolized by HNMT.²⁹
PMAT and OCT 1 through 3 are polyspecific transporters. They transport various monoamines, including serotonin, dopamine, norepinephrine, and histamine.
Unlike catecholamines (e.g., DAT, NET) and serotonin (SERT), no high-affinity “uptake 1” transporter has yet been identified for histamine. While “Uptake 1” transporters typically exhibit strong affinity with K_m values below 5 μM, the affinity of “Uptake 2” transporters is considerably weaker, with K_m values (here: for histamine) of at least 100 μM.²⁹ PMAT and OCT 1 through 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 PMAT can be found at Dopamine Reuptake by the Plasma Membrane Monoamine Transporter (PMAT) in the article Dopamine Reuptake, Dopamine Degradation

³¹ e PMAT (encoded by the SLC29A4 gene), discovered in 2004, is widely distributed in the human brain and appears to be involved not only in histamine reuptake but also in the clearance of dopamine and serotonin.¹⁸
PMAT plays a significantly greater role in histamine reuptake than OCT3²⁸ in human astrocytes.²⁹
It remains unclear whether PMAT reabsorbs histamine not only in astrocytes but also presynaptically in histamine neurons.
The IC₅₀ for histamine is at least 100 μM.²⁹
PMAT gene polymorphisms associated with reduced transport activity for the monoamines serotonin and dopamine, as well as the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), are correlated with autism spectrum disorders (ASD).³²
PMAT-KO mice (which are therefore deficient in PMAT) show neither a significant 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 explanation of OCT can be found at Dopamine Reuptake by Organic Cation Transporters (OCT) in the article Dopamine Reuptake, Dopamine Degradation

The Km value of OCT3 for histamine is at least 100 μM.²⁹
It remains unclear whether OCT3 reuptakes histamine not only in astrocytes but also presynaptically in histamine neurons.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 reabsorbs histamine; however, it has not been detected in human astrocytes,²⁸ whereas OCT1 (SLC22A1) has been found in the human brain, OCTN1 (SLC22AN1), and OCTN2 (SLC22AN2).³⁴
Human OCT2 transports:²⁹

• Cations
  • Tetraethylammonium
  • 1-Methyl-4-phenylpyridinium (MPP)
• Medications
  • Cimetidine (H2R antagonist)
• Neurotransmitters
  • Histamine
  • Acetylcholine
  • Dopamine
  • Norepinephrine
  • Serotonin
    OCT2 is found in the brain at presynaptic nerve terminals 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
  • yet functionally significant as H2R
• postsynaptic²⁹
  • on non-neuronal target cells (like H2R, unlike H3R)²
• low histamine affinity³
• is expressed in various cell types, including mast cells³
• involved in Type 1 hypersensitivity reactions³
• linked 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
  • enabled⁷
    • AMP kinase
    • Nuclear factor kappa B
    • Nitric oxide synthases
    • Phospholipase A2 (PLA2)
      • induces the formation of arachidonic acid
• Scope of regulation
  • systemic vasodilation (widening of blood vessels)
  • Skin redness
  • Day-night rhythm
    • Mice lacking the H1 receptor have a disrupted day-night rhythm and are not awakened by H3 antagonists.⁶
    • Sleep³⁵
  • Vomiting
  • Bronchoconstriction
  • Neurotransmission
  • possibly antidepressant
  • possibly anticonvulsant
  • may suppress appetite
• Agonists
  • Histamine
  • Histaprodifen (selective agonist)
• Antagonists
  • All H1 antihistamines 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 common as H1R⁷
  • yet functionally less significant than H1R
• postsynaptic²⁹
  • on non-neuronal target cells (like H1R, unlike H3R)²
• low histamine affinity³
• linked to⁷
  Gas¹
• 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 Ca2+-activated potassium conductance⁷
• inhibits PLA2⁷
• inhibits the release of arachidonic acid⁷
• Scope of regulation
  • Aggression³⁸
  • Improvement of motor balance and motor coordination via H2 receptors in the cerebellum³⁹
  • Motor activity and exploratory behavior are increased via H2 receptors, not via H1 receptors⁵
  • Anxiety is primarily increased via H2R and only secondarily via H1R⁵
  • is primarily involved in cytokine production by Th1 lymphocytes³
  • Gastric acid secretion
  • Reflex tachycardia
• Agonists
  • Histamine
  • Betazol
  • Amthamines²
  • Dimaprit²
  • Impromidine²
• Antagonists
  • Cimetidine
  • Famotidine
  • Ranitidine
  • Roxatidine
  • Nizatidine²

5.3. H3 histamine receptor¶

• high histamine affinity³
• almost exclusively in the brain, with only a few in the heart¹
  • frequently in⁴⁰
    • particularly in dopamine-rich areas such as
      • dorsal striatum
        • The vast majority of H3R is found postsynaptically in the dorsal striatum on medium-sized spiny output neurons⁴¹⁴⁰
        • 95% (+/- 12%) of all D1-positive cells and 89% (+/- 12%) of all D2-positive cells in the striatum also express 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 commonly)⁷²⁹
    • on⁷
      • Soma
      • Dendrites
      • Axons
  • not on all histaminergic neurons¹
    • presynaptic = negative feedback that inhibits the synthesis and release of the neurotransmitter produced by the respective neuron
    • apparently present in the TMN, the Meynert nucleus (nucleus basalis magnocellularis), and the cortex, but not in the dorsal and ventral striatum or the nucleus accumbens⁴⁴⁴⁵
  • also presynaptically on terminals of non-histaminergic neurons¹ (presynaptic heteroreceptor)²
  • In contrast, H1R and H2R are found on non-neuronal target cells² Therefore, only H3R is relevant to the action of histamine as a neurotransmitter
  • Other sources describe H3R solely as an autoreceptor²⁹
• long (postsynaptic)
  • Most H3R receptors are located postsynaptically on cells outside the neuronal histaminergic system²’
  • can be found at
    • other neurons, including glutamate, acetylcholine, GABA (heteroreceptor), the vast majority⁷²
    • on the axons of other nerve cells² in the basal ganglia⁷
    • is found primarily in the dorsal and ventral striatum
• H3R, as well as HNMT, H1R, and H2R, appear to be frequently up- or down-regulated in ASS.⁴⁶
• Signal paths:⁷
  • primarily linked to Gi/o¹
    • inhibits adenylate cyclase and activates Ca²⁺ channels
    • thereby regulates histamine synthesis and neurotransmitter release
    • very high constitutive activity:³⁶
      • Gi/o protein remains continuously activated, even when 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
  • also plays a secondary role in Gq/11 signal transduction¹
    • activates PLA2
    • activates active glycogen synthase kinase-3 (GSK3)
    • activates MAP kinase signaling pathways
  • Inhibition of the Na+/H+ pump
  • Activation of G-protein-coupled inward-directed K+ channels
  • Activation of phospholipase C
  • regulates the mitogen-activated protein kinase (MAPK) pathway
  • regulates the phosphatidylinositol-3-kinase (PI3K) pathway
• Scope of regulation
  • Neurotransmission
    • H3 antagonists increase the release of histamine (autoregulation) ⁵
    • H3R agonists
      • inhibit acetylcholine²
      • inhibit norepinephrine²
      • inhibit serotonin²
      • inhibit dopamine²
    • Glutamate
  • Regulation of circadian rhythms
  • plays a role 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, thereby promoting arousal and cognition⁴⁷

  • appear to increase dopamine levels in the frontal cortex, whereas agonists decrease dopamine levels, at least when combined with dopaminergic drugs¹

  • Ciproxifan

  • Thioperamide

    • Parkinson’s⁴⁸
    • increases motor activity / exploratory behavior⁵
    • increased anxiety⁵

  • Pitolisant (antagonist/inverse agonist); Wakix® (pitolisant hydrochloride)⁴⁸, selective H3R antagonist/inverse agonist⁴⁹

    • Narcolepsy, sleep disorders
      • In narcolepsy, significantly reduced levels of histamine were found in the brain⁵⁰
    • No impact on:⁴⁹
      • striatal dopamine
        • unlike AMP, modafinil, and solriamfetol
      • Locomotion
        • even reduced the hyperlocomotion triggered by modafinil or solriamfetol
      • Food intake

  • H3RA 2-18⁴⁸

    • Epilepsy

  • Clobenpropit (antagonist, inverse agonist)

    • appeared to directly inhibit dopamine reuptake in vitro, as well as, to a slightly lesser extent, norepinephrine reuptake in striatal and cerebrocortical synaptosomes⁵¹

  • Iodophenpropit

    • appeared to directly inhibit dopamine reuptake in vitro, as well as, to a slightly lesser extent, 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

    • demonstrated full efficacy in the five-trial inhibitory avoidance learning model in rat pups at a dose of 0.1 mg/kg
    • Full efficacy in the social recognition memory model in adult rats at 0.01 mg/kg.
    • did not stimulate locomotor function
    • few 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-dimethylpyrrolidin-1-yl)propoxy)biphenyl-4-yl)morpholin-4-ylmethanone))⁵⁵

  • A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone]⁵⁶

    • improved cognitive performance in a five-trial avoidance test for young rats (10 mg/kg); similar in magnitude to that observed with thioperamide (10 mg/kg), Ciproxifan (3 mg/kg) and GT-2331 (1 mg/kg)⁵⁷
    • Social memory in adult rats was significantly improved by doses of 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 young rats (3 mg/kg); similar in magnitude to that observed with thioperamide (10 mg/kg), Ciproxifan (3 mg/kg), and GT-2331 (1 mg/kg)⁵⁷
    • Social memory in adult rats was significantly improved at doses of 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 in a dose-dependent and selective manner to the histamine H3 receptor in the frontal cortex
    • elevated levels of extracellular histamine in the posterior hypothalamus
    • elevated levels of dopamine and acetylcholine in the medial prefrontal cortex
    • improved cognition
    • reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test at doses of 0.03 to 0.3 mg/kg, administered orally
    • Stimulant effects at 3 to 10 mg/kg, administered orally

  • ST-713

    • H3 antagonist (Ki = 1.21 nM)
    • D2 antagonist (Ki = 41 nM)
    • D3 antagonist (Ki = 50 nM)
    • low affinity for other receptors
      • H1 (Ki = 205 nM)
      • H4 (Ki = 210 nM)
      • D1 (Ki = 232 nM)
      • D5 (Ki = 105 nM)
    • reduced autistic-like behavior in male BTBR T+tf/J mice.⁵⁸⁵⁹
      • ST-713 (3-(2-chloro-10H-phenothiazine-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine) showed improved efficacy at 2.5, 5, and 10 mg/kg, i.p., in a dose-dependent manner
        • social deficits
        • repetitive/compulsive behaviors
        • anxiety disorders
        • but not the hyperactivity of the tested mice
        • 5 mg reduced the elevated protein levels in the hippocampus and cerebellum of
          • NF-κB p65
          • COX-2
          • iNOS
        • Concomitant administration of an HR agonist or an anticholinergic agent reversed the improvement in social parameters

  • ST-2223⁶⁰⁶¹

    • H3R/D2R/D3R receptor antagonist
    • Doses of 2.5, 5, and 10 mg/kg, administered intraperitoneally, significantly and in a dose-dependent manner alleviated social deficits and anxiety-like behaviors in BTBR mice
    • Increase in 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 found primarily 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 in neurons (presumably due to limitations in detection methods)
• Approximately 40% homology to H3R⁷
• Signal paths:⁷
  • Gi/Go-coupled GPCRs
    • reduces cAMP accumulation
    • reduces adenylate cyclase activity¹
  • increases Ca2+ mobilization
  • activates kinases (ERK, PI3K, and MAPK)
  • activates transcription factor-activating protein-1
• Scope of Regulation
  • Mast cell chemotaxis
  • Inflammation⁶⁴
    • H4R stimulation increases histamine and cytokine production³
  • Pain⁶⁵⁶⁶⁶⁷
• Agonists
  • Histamine
  • 4-methylhistamine
  • Immepip⁶⁸
  • Clobenopropit (partial agonist)²
  • Clozapine³⁶
• Antagonists
  • Thioperamide²
  • JNJ-7777120
    • Inhibits pro-inflammatory microglia and the progression of Parkinson’s disease in a 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 complexes composed of multiple receptors for different neurotransmitters.
Histamine receptors form heteromers, including the following:⁷¹
H3R/Dopamine D2R
H3R/Dopamine D1R
H3R/Adenosine A2A

While D1R is normally coupled to adenylate cyclase via the Gs protein, this changes to a Gi/o coupling when the D1 dimer dimerizes with the H3 receptor.⁷²
While H3R and D1R act in opposition to each other when isolated—because D1R is coupled to a Gs protein and H3R to a Gi/o protein—they act synchronously as a heteromer, just like H3R. While dopamine normally enhances the activity of the direct pathway via D1R, it inhibits those cells in 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 it has been demonstrated that these heterodimers do indeed exist in vivo (Moreno et al., 2011), it is currently unknown how prevalent they are and to what extent they contribute to the overall effect of dopamine in the dorsal striatum.

6. Effects of Histamine¶

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

• IgE-mediated release (allergic reaction)
  • After the allergen binds to the cell surface, histamine is released from the secretory granules of mast cells through the cross-linking of IgE antibodies
• IgE-independent release (non-allergic)⁷³
  • is regulated by the cyclic nucleotides cAMP and cGMP as “second messengers”
  • Histamine or beta-adrenergic stimulants increase cAMP concentration
    • cAMP inhibits mast cell degranulation
  • Histamine release is increased by
    • α-adrenergic and cholinergic effects
      • lowers cAMP
      • promotes the release of histamine
    • certain inflammatory cytokines
    • Binding of the complement factors C5a and C3a to receptors on mast cells
  • “Non-allergic” histamine releasers may include
    • Medications
    • Food
    • chemical irritants
    • physical stimuli
    • Hypoxia
    • Neuropeptides
    • Enzymes
      • Phospholipase

Among other things, histamine causes:²

• increased permeability of the capillaries. This allows white blood cells and certain proteins (e.g., glycoproteins such as immunoglobulins) to enter infected tissues to fight pathogens there.
• Itching as a consequence of direct stimulation of sensory (pain) nerve endings
• Activation and migration of endothelial cells, which is essential for angiogenesis.

The human gut microbiota can also produce histamine.²

Effects of Histamine

• in the brain⁷
  • Arousal
  • Awakening
    • Activation of TMN neurons promotes alertness
    • During non-REM (non-rapid eye movement) sleep, TMNs fire only sparingly
    • During REM (Rapid Eye Movement) sleep, TMNs are inactive
  • Maintaining vigilance³⁵
  • Learning and Memory⁷⁷⁴⁶

    • Histamine appears to play an important role in learning and memory via H1R and H2R receptors

    • HDC-deficient mice exhibit

      • specific changes in task-related learning and memory
      • improved performance in passive avoidance and fear memory
      • a gender-specific deficit or an improvement in the ability to recognize water mazes and new locations

    • Pharmacological blockade of H1R impairs

      • spatial memory
      • the consolidation of object recognition memory
      • avoidance memory

    • H2R antagonists block the consolidation of object recognition memory and inhibitory avoidance memory

    • Histamine improves both spatial working memory and reference memory through H1R and H2R receptors in the radial labyrinth task following scopolamine-induced memory deficits

    • The formation or retrieval of memories requires a certain level of tonic TMN activity.

      • It is possible that enhancing histaminergic signaling in the brain could promote the recovery of seemingly lost memories⁷⁵

    • H1R- or H2R-knockout mice exhibit

      • Difficulties with object recognition
      • Difficulties in developing spatial memory
      • Improvements in auditory and contextual freezing

    • H1R knockout mice also show

      • severe impairments in the memory of chronological sequences

      • Feeding

      • Energy

    • H3R antagonists

      • demonstrate a protective effect against various cognitive impairments in the Y-maze, object recognition, passive avoidance, radial arm maze, and water maze tests
      • The enhanced detection caused by the H3R antagonist ciproxifan appears to be at least partially dependent on H1R and H2R
      • showed improvements in memory in patients with Alzheimer’s
• Immune system⁷⁶
  • Histamine stimulates the recruitment of mast cells and basophils to the site of inflammation
    • Response to various stimuli, such as allergens, pathogens, and stress
  • in the innate immune system
    • intensifies the inflammatory response
    • may promote the development of chronic inflammation, apparently via H1R
  • adaptive immune response
    • Histamine regulates adaptive immune responses at the systemic level (i.e., the 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; the same applies depending on the stage of development of the CNS²
• the digestive system⁷⁶
  • H2R antagonists have a gastroprotective effect
    • Gastritis
    • gastroesophageal reflux
    • Prevention and treatment of peptic ulcers and bleeding associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs)
• Social behavior
  • H3R antagonists showed improvements in autistic behaviors
• Migraine
  • Histamine has a vasodilatory effect
  • Migraine attacks are less common in the evening, which correlates with lower central histaminergic activity
  • Histamine plays a role in the pathogenesis of migraine through inflammatory pathways
  • plays a crucial role through an inflammatory pathway
    • H3R agonists are believed to have antinociceptive and antineurogenic 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
  • Histamine inhibits excitatory potentiation on D1(+)-MSNs via presynaptic H3 receptor-dependent long-term depression, which requires Gβγ-mediated Akt-GSK3β signaling
  • Histamine asymmetrically regulates glutamatergic transmission from the PFC and the mediodorsal thalamus, with inputs from the PFC cortex undergoing robust long-term depression mediated 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 also affect

• Learning and memory processes⁷⁸
• Thermoregulation⁷⁸
• Satiety (caused by 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, whereas 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 through H2 receptors and, to a lesser extent, through H1 receptors⁵

7. Factors That Affect Histamine¶

The release of histamine in brain neurons is increased by²

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

8. Disorders of the histamine system¶

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

• Narcolepsy
  • In narcolepsy, significantly reduced levels of histamine in the brain were found⁵⁰
• Hallucinations
• Schizophrenia-like conditions
  To date, no evidence has been found that histamine itself plays a role in schizophrenia.⁸⁰
• Sleep problems
  • Histamine neurons⁷
    • stop the firing of neurons during the transition from wakefulness to sleep
    • remaining silent during slow-wave sleep and REM sleep
    • Resume firing after regaining consciousness
    • Lowest power consumption in wakeful idle mode
    • moderate breathing while awake
    • Maximum output with high vigilance
  • HDC knockout mice (impaired histamine synthesis) show
    • Sleep fragmentation
    • increased REM sleep during the light period
    • significant deficits in alertness as darkness sets in
  • H1 receptor antagonists can help with insomnia⁸⁰
  • H1R antagonists promote sleep
  • Mechanisms by which histamine affects sleep:⁷
    • The ventrolateral preoptic nucleus (VLPO) is associated with the promotion of sleep
    • Histamine indirectly inhibits VLPO neurons by activating GABAergic interneurons, which in turn disinhibits histaminergic neurons to promote wakefulness
    • Histaminergic axons release GABA paracrinally in the neocortex to prevent overactivation by histamine and to regulate the level of alertness
    • Histamine can also directly modulate glutamatergic neurons in the thalamus and induce 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 to the cortex
    • The hypocretin system largely maintains wakefulness through histaminergic neurons
    • HCRT neurons and histaminergic neurons
      • are located next to each other in the human hypothalamus
      • overlap in their projections
      • HCRT neurons directly excite histaminergic neurons via the HCRT-2 receptor
    • Histamine may regulate HCRT neurons via the H1R
      • The H1R antagonist pyrilamine inhibits HCRT-induced excitation in rats
      • H1R knockout mice do not show an HCRT-induced increase in wakefulness
• Tourette’s (rare)
• Alzheimer’s and Parkinson’s
  • High histamine levels in the substantia nigra correlate with a reduced number of dopaminergic cells
  • It appears that the H1 receptor is involved⁸⁰
• Huntington
• Depression
  • reduced H1 receptor binding

8.1. Histamine Deficiency¶

• Tourette’s syndrome⁸¹⁸²
  Histidine decarboxylase knockout mice (HDC-KO) exhibit stereotypical locomotor behaviors that reflect the core phenomenology of Tourette syndrome.⁸³
• Rare variants of the histamine receptor gene appear to be involved in Tourette syndrome and autism spectrum disorders.⁸⁴⁸⁵
• A deficiency of histamine H2 receptors on parvalbumin-positive neurons in the substantia nigra pars recticulata⁸⁶
  • weakens the neural activity of these neurons
  • causes hyperactivity, impulsivity, and inattention in mice
  • In people with ADHD and in mice with DAT deficits, reduced H2R expression was observed on parvalbumin-positive neurons in the substantia nigra pars recticulata
    • H2R agonists improved their ADHD symptoms

8.2. Excess Histamine / Histamine Intolerance¶

8.2.1. The Development of Histamine Intolerance¶

A very good explanation of histamine intolerance can be found atwww.histaminintoleranz.ch (German, English, French).

Histamine intolerance is caused by an excess of histamine relative to histamine breakdown.
An excess of histamine can have various causes:

• excessive histamine intake (food, fish poisoning)
• insufficient histamine breakdown
  • most commonly diamine oxidase deficiency (peripheral)
  • HNMT deficiency (CNS)
• Smoking appears to increase histamine levels^8788899091
  Histamine moderates reactions to cigarette smoke.⁹² Reports suggesting that smoking lowers histamine levels⁹³ or leaves them unchanged⁹⁴ are, however, the exception. It is conceivable, however, that smoking increases the reaction to histamine.^95969798
• Another possible cause is systemic mast cell activation disorder (MCAD)
  In this condition, pathologically altered mast cells (a type of immune cell that defends against foreign substances) produce histamine and other signaling substances (mediators). The prevalence of MCAD is estimated to be between 1 and 17 percent.⁹⁹
  Excellent overview of MCAD at <https://www.mastzellaktivierung.info/>¹⁰⁰
  MCAD acts primarily, but not exclusively, through histamine.
  • Types of MCAD:
    • Mast Cell Activation Syndrome (MCAS)
    • systemic mastocytosis (SM) (rare)
    • Mast cell leukemia (MCL) (rare)
  • Mechanisms of action of an MCAD:¹⁰¹
    The percentages reflect the consensus that the mediators listed play a role in MCAD.
    • Histamine
      • Headaches
      • low blood pressure
      • Hives (red welts, urticaria)
        • with or without angioedema (sudden, painless swelling)
      • Itching (pruritus)
      • Diarrhea
    • Prostaglandin D2 (PGD2) (95%)
      • Mucus secretion
      • narrowed airways (bronchoconstriction)
        • in conjunction with thromboxane and PGF2α
      • Vascular instability (dilatation of blood vessels)
      • sleep-inducing
      • Reduces body temperature
      • a possible cause of hereditary hair loss in men, along with the steroid hormone dihydrotestosterone (DHT)¹⁰²
    • PAF2 (platelet-activating factor) (90%)
      • Abdominal cramps
      • Pulmonary edema
      • Urticaria
      • Bronchoconstriction
      • Hypotension
      • Heart rhythm disorders
    • 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 followed by inflammatory reactions
    • Leukotrienes¹⁰³
      • allergic reactions
      • Inflammatory reactions

Elevated histamine levels cause pseudoallergic symptoms. These symptoms vary greatly from person to person, making it very difficult to diagnose the condition based on a list of symptoms.

8.2.2. Prevalence of Histamine Intolerance¶

The prevalence is 1% of the population. 80% of the people with ADHD are middle-aged women, and 20% are men.⁷³
More recent studies have found higher prevalence rates.

8.2.3. Possible symptoms of histamine intolerance¶

• Skin
  • Skin redness
  • Hives
  • Eczema
  • Itching[7]
• Head
  • Headaches
  • Sensation of heat
  • Migraine
  • Dizziness
• Respiratory tract
  • stuffy or runny nose
  • Difficulty breathing
  • Bronchial asthma
  • Sore throat
• Digestive system
  • Bloating (flatulence)
  • Diarrhea
  • Constipation
  • Nausea/vomiting
  • Stomach pain
  • Stomach pain
  • Heartburn
• Cardiovascular system
  • Changes in blood pressure
    • High blood pressure (hypertension)
    • low blood pressure (hypotension)
  • Rapid heartbeat (tachycardia)
  • Heart rhythm disorders
• Urology
  • Menstrual cramps (dysmenorrhea)
  • Cystitis
  • Urethritis
  • Mucosal irritation of the female genitalia
• Tissue
  • Fluid retention (edema)
  • Bone marrow edema (BME)
  • Joint pain
• Energy balance
  • States of exhaustion
  • Seasickness
  • Fatigue
  • Sleep Disorders
• Mental symptoms
  • Confusion
  • Nervousness
  • depressive moods

8.2.4. Foods That Increase Histamine Levels¶

A list of foods that increase histamine levels can be found at ¹⁰⁴
There are various ways in which foods can increase histamine levels.

8.2.4.1. Effects of Elevated Histamine Levels¶

8.2.4.1.1. Containing histamine¶

Foods that contain histamine raise histamine levels.

8.2.4.1.2. Histamine-releasing agents¶

Some foods cause an increased release of histamine from storage 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 them down, which means that less DAO is available to break down histamine.

8.2.4.1.5. Increased intestinal permeability to 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 the causes of MCAD can be found at <https://www.mastzellaktivierung.info/>¹⁰⁵

Quade, Bailly, Bartling, Bliesener, and Springer list foods with high histamine levels in their book Histamine Intolerance.¹⁰⁶ This list applies only to foods with high histamine content, not, for example, histamine liberators or DAO-inhibiting substances.

8.2.5. Treatment of Histamine Intolerance¶

The first-line treatment is a low-histamine diet.

Often, even a one-month strict low-histamine diet is enough to completely deplete histamine stores. Afterward, limited consumption of certain histamine-raising foods is usually possible. Smoking significantly raises histamine levels and thus undermines the low-histamine diet.⁸⁸

In addition, the missing DAO enzyme can be taken 15 to 30 minutes before meals. Taking DAO can only compensate for the occasional “indulgence,” but it cannot replace a healthy diet altogether.

9. Histamine and ADHD¶

There is barely any evidence of a correlation between histamine intolerance and ADHD. A search on NCBI/PubMed for “histamine intolerance ADHD” did not yield a single article.¹⁰⁷

Taking antihistamines (especially first-generation H1R antihistamines) during early childhood appears to significantly increase the risk of developing ADHD later in life. A possible cause cited is a disorder of REM sleep, which in turn impairs brain maturation.^108109110
According to another study, previous use of antihistamines increased ADHD symptoms in people with atopic dermatitis.¹¹¹

Food additives (in this case: Sun Yellow, Carmoisine, Tartrazine, Ponceau 4R, Quinoline Yellow, Allura Red, sodium benzoate) can cause the release of histamine from circulating basophils. This process is non-allergic, meaning it does not depend on immunoglobulin E. The increased release of histamine can—in individuals who carry certain gene variants encoding histamine-degrading enzymes—exacerbate ADHD symptoms.¹¹²

A report on four individual cases of children with learning disabilities and ADHD describes a significant improvement in ADHD symptoms following treatment with antihistamines.¹¹³

The H3 histamine receptor is thought to be involved in arousal, regulation of pituitary hormone release, cognitive functions, motivation, goal-directed behavior, memory, and the sleep-wake cycle. However, clinical trials of H3 receptor drugs for ADHD (MK-0249, Bavisant, PF-03654746) were unsuccessful in Phase 2 studies or were discontinued in Phase 2 (betahistine).¹¹⁴

9.1. Histamine Levels Are Often Elevated in ADHD¶

A case study reports a single case in which methylphenidate caused chronic eosinophilic pneumonia. After discontinuing MPH and the pneumonia had subsided, it recurred upon resuming MPH, accompanied by skin redness (rash).¹¹⁵ A rash can be a sign of histamine intolerance. Eosinophils are closely linked to the histamine system.
30% of children with ADHD had elevated urinary histamine levels. However, the histamine levels did not correlate with the severity of ADHD symptoms.¹¹⁶

A histamine deficiency could also contribute to a dysregulation of the dopamine system.¹¹⁷

9.1.1. Histamine Breakdown by DAO Is Often Reduced in ADHD¶

A Spanish study found that 82.1% of 40 children with ADHD had genetically reduced diamine oxidase (DAO) activity, and in 15.2%, a significantly reduced level of DAO activity (and thus reduced histamine breakdown, leading to elevated (peripheral) histamine levels).⁷⁶ The study is set to be expanded to include 200 children with ADHD and 100 controls. DAO is also known as ABP1.
Among 303 children with ADHD, 78.8% had at least one less 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 mixed effect on IQ—partly negative and partly positive.¹¹⁸

9.1.2. Histamine Breakdown by HNMT Is Often Reduced in ADHD¶

Furthermore, a correlation between ADHD and reduced histamine N-methyltransferase (HNMT) is described, which also leads to reduced histamine breakdown and elevated histamine levels.¹⁸
Various HNMT gene polymorphisms are relevant in ADHD and other disorders:

• Thr105Ile (rs11558538) showed¹¹²
  • reduced thermal stability
  • reduced activity of HNMT¹¹⁹, resulting in reduced histamine degradation
  • Food additives have a more adverse effect on ADHD symptoms in 3-year-olds and 8- and 9-year-olds
  • a reduced risk of Parkinson’s disease¹²⁰
• T939C showed
  • increased hyperactivity¹¹²
  • a greater adverse effect of food additives on ADHD symptoms in 3-year-olds and 8- and 9-year-olds¹¹²

Other gene variants and their effects on HNMT enzyme activity are known, but there are no reports of a correlation with ADHD:

• G179A showed
  • impaired HNMT enzyme activity
  • intellectual disability²⁰
• C314T showed
  • reduced HNMT enzyme activity
  • The Km value for histamine is increased by a factor of 1.3 (= lower binding affinity)
  • The Km value for SAM was increased by a factor of 1.8 (= lower binding affinity)
  • No correlation with asthma or rhinitis
• T632C showed
  • impaired HNMT enzyme activity
  • intellectual disability²⁰
• A939G (also known as C939T/rs1050891)¹¹² shows
  • increased HNMT mRNA stability
  • increased HNMT enzyme activity¹²¹

9.2. Histamine and Dopamine¶

Animal studies have found a correlation between high histamine levels in the substantia nigra and the loss of dopaminergic cells, which leads to reduced dopamine levels.¹⁹ To date, no therapeutic benefit of H3 antagonists (which lower histamine levels and increase dopamine levels) has been found for Alzheimer’s disease or ADHD.⁸⁰

Receptor heteromers:⁷

• H3R - D1R - Heteromers
  • D1R activation inhibits the production of cAMP, rather than stimulating it as is usually the case
  • H3R activation should reduce D13 affinity
• H3R - D2R - Heteromers
  • appear to merely reduce the receptor’s affinity for dopamine

The histaminergic system appears to be closely linked to the dopaminergic system and synaptic transmission in the striatum (compiled from Hu and Chen (2017), unless otherwise noted):⁷

• H3 antagonists/inverse agonists increase the release of dopamine
  • in the prefrontal cortex⁵³ in the presence of dopaminergic drugs or medications¹ and ACC¹²²
  • but not in the dorsal or ventral striatum (where it remains unchanged)^{5344 1} , or nucleus accumbens^12312470
  • but it did increase dopamine release in the nucleus accumbens in response to methamphetamine¹²⁴¹²⁵
  • H3R appear in the striatum¹
    • to enhance the dopamine (D2R)-induced inhibition of the indirect pathway (since both are coupled to a Gi/o protein)
      • H3R agonists, like D2R agonists, reduce GABA levels in the striatum, while
    • to inhibit dopamine (D1R)-induced activation of the direct pathway (since D1R is coupled to a Gs protein and H3R is coupled to a Gi/o protein)
      • D1R agonists enhance GABA
      • H3R agonists may inhibit D1R agonists¹²⁶ via a postsynaptic mechanism¹
• Histaminergic neurons can also release dopamine (or GABA)
  • The synergistic effects of ciproxifan and haloperidol suggest a direct, functional H3/D2 receptor interaction in striatopallidal neurons, suggesting that H3R antagonists could be useful tools for improving the symptomatic treatment of schizophrenia
• Histamine can selectively activate microglia, leading to increased inflammation—a hallmark of PD pathology—and damaging dopaminergic neurons in the SNc
• The H3R agonist Immepip alleviates the apomorphine-induced rotatory behavior in rats with 6-hydroxydopamine (6-OHDA) lesions
• Concomitant administration of Immepip or Imetit with L-DOPA alleviates L-DOPA-induced dyskinesia or chorea, but not dystonia
• Intranigral injection of Immepip increases twisting behavior following systemic apomorphine administration in rats
• The H3R antagonist thioperamide alleviates apomorphine-induced stereotyped behavior in rats with 6-OHDA lesions
• The H3R antagonist pitolisant alleviates excessive daytime sleepiness in patients with Parkinson’s disease; motor function remains unchanged.
• Histamine H2R levels in the striatum of patients with Parkinson’s disease remain unchanged. 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 adjuncts in the treatment of Parkinson’s disease.
• The TMN contains a group of dopaminergic neurons that share electrophysiological properties with histaminergic neurons
• H3Rs are expressed on GABAergic input terminals from the substantia nigra reticulata. Stimulation of these receptors reduces GABA release, which results in increased excitation of dopaminergic cells in the substantia nigra pars compacta
• Histamine inhibits dopamine release in the striatum of mice via H3R, unlike H3R antagonists
• H3R regulate the striatum¹²⁷
• Most H3R in the dorsal and ventral striatum are located postsynaptically on medium-sized spiny output neurons. These cells also contain a large number of D1R and D2R. H3R form receptor heterodimers with D1R and D2R.¹
• More than 85% of D1R- and D2R-expressing MSNs in the dorsal and ventral striatum contain H3R¹²⁸
• H3R antagonists (GT-233, 1 mg/kg s.c. and ciproxifan, 3 mg/kg s.c.) significantly and in a dose-dependent manner improved the learning performance of SHR pups, as did methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (an agonist at nicotinic acetylcholine receptors, 0.03 mg/kg s.c.). The H3R agonist (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the cognitive-enhancing effect of ciproxifan.¹²⁹
• an H3R antagonist¹³⁰
  • attenuated the D1R-induced cell death signaling and neuronal degeneration observed in Huntington’s disease
  • reduced cognitive and motor learning deficits and the loss of D1R-H3R heteromer expression in a mouse model of Huntington’s disease
• Histamine stimulates dopamine D1R- and D2R-expressing neurons in the striatum with equal intensity. This occurs via postsynaptic H1R and H2R receptors.¹³¹
• The H3R agonist α-methylhistamine reduced dopamine release in the ventral (but not the dorsal) striatum by decreasing the activity of striatal cholinergic interneurons¹³²
• H3R is expressed, along with D1R, by striato-nigral medium spiny GABAergic neurons, where it functionally antagonizes D1R-mediated responses⁶⁸
• H3R agonists modulated activity in D2R-SPNs (but not in D1R-SPNs)¹²⁸
  • 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 motor activity and stereotyped behavior induced by D2R agonists¹²⁸
• H3R-knockout fish exhibit reduced dopamine and serotonin levels¹³³
• Histamine inhibits both cortical and thalamic excitatory projections to MSNs via presynaptic H3R receptors
• Histamine can selectively modulate the dynamics of thalamostriatal synapses to facilitate thalamic inputs
• Histamine depolarizes both classes of MSNs through the action of the H2R
• Histamine suppresses lateral feedback inhibition between MSNs via the H3R or H2R
• The effect of H2R may be caused indirectly by the activation of H2R in cholinergic interneurons, thereby increasing acetylcholine release in the striatum
• H1R and H2R are co-localized on D1R- and D2R-expressing MSNs and mediate the histamine-induced excitation of both types of neurons¹³¹
• Genetically determined histamine deficiency causes an upregulation of dopamine neurotransmission¹³⁴
• Increased histaminergic innervation of the entopeduncular nucleus (EPN) in a mouse model of Parkinson’s disease activates parvalbumin neurons (PV) in the EPN, which project via hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that are coupled to postsynaptic H2R and project to the thalamic motor nucleus. Presynaptic H3R activation in the glutamatergic neurons of the subthalamic nucleus (STN) that project to the EPN inhibits this process. Activation of both receptor types improves the motor dysfunction associated with parkinsonism. Pharmacological activation of H2R, as well as genetic upregulation of HCN2 in EPNPV neurons—which reduce neuronal burst firing—improve the motor dysfunction associated with parkinsonism, independent of changes in neuronal firing rate. Optogenetic inhibition of EPNPV neurons and the pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons improve Parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons.¹³⁵
• In embryos, histamine appears to reduce dopaminergic gene transcription by altering several epigenetic components associated with DNA and histone modifications, which affects the development of mDA neurons during development. Histamine had a long-term effect on the formation of the nigrostriatal and mesolimbic/mesocortical pathways. Histamine caused:¹³⁶
  • a significant decrease in TH immunoreactivity in the midbrain
  • Changes in dopaminergic neuronal fibers
  • a significantly smaller TH-positive area in the forebrain in whole-body staining
• HDC-KO mice lack the histamine-producing enzyme histidine decarboxylase (HDC) and, consequently, histamine. HDC-KO mice exhibited:¹³⁷
  • a distinct behavioral pattern when exploring a new environment, particularly
  • an increased frequency of sitting up against the wall, jumping, and shaking the head or body.
  • reduced dopamine and serotonin levels in the striatum
  • elevated levels of DOPAC, a dopamine metabolite
  • reduced gene expression of dynorphin and enkephalin
  • increased striatal dopamine turnover following treatment with the dopamine precursor L-dopa
• An HNMT inhibitor reduced dopamine and histamine turnover in the striatum, the nucleus accumbens, and the hypothalamus¹³⁸
• Dopamine modulation of the basal ganglia appears to be gender-specific:¹¹⁷
  • Histamine in the cerebral ventricles (intracerebroventricular) caused
    • reduced dopamine levels in the striatum of male mice
      • The effect was dependent on H2R in the substantia nigra pars compacta (SNc)
      • Knockdown of H2R in GABAergic SNc neurons reversed the effect
    • Elevated dopamine levels in the striatum of female mice
      • H2R did not affect the effect of histamine on dopamine
      • H3R agonists in the striatum increased dopamine levels in the striatum
      • The effect of histamine on dopamine was modulated by the estrus cycle in females; it occurred only during proestrus, when estrogen levels are high, and during estrus

9.3. Habenula, ADHD, and Histamine¶

Early-life lesions of the habenula cause behavioral and brain changes similar to those seen in ADHD.¹³⁹
Histamine H3 receptor antagonists relieve these symptoms.¹⁴⁰

The Habenula

• transmits limbic information to the midbrain monoamine system
  • is thus involved in regulating the release of monoamines in target brain regions such as the striatum, where some of the biological substrates involved in processing the perception of time are located.
• is part of the circadian rhythm network and plays a role in sleep regulation

ADHD is often associated with changes in the circadian rhythm, sleep disturbances, and alterations in the perception of time.

9.4. Histamine in the Spontaneously Hypertensive Rat (SHR)¶

The SHR is the most commonly used animal model for ADHD.
Compared to WKY, the SHR showed:¹⁴¹

• Histamine
  • increased in
    • Hypothalamus (anterior and posterior) of young and adult SHR
    • Brainstem of a young SHR
  • unchanged in
    • Cortex-midbrain
      • but higher in adult WKY and SHR mice than in young ones
  • reduced histamine metabolism in:¹⁴²
    • Hypothalamus
    • Brainstem
    • Chronic administration of L-histidine did not affect high blood pressure in SHR rats
      • Additionally: Chronic administration of L-histidine (100 mg/kg twice daily for 4 weeks) to young SHR mice prevented the age-related increase in blood pressure and urinary norepinephrine levels typical of SHR mice.¹⁴³
  • increased release of histamine from mast cells¹⁴⁴¹⁴⁵
    • with reduced nitric oxide release from mast cells¹⁴⁴
• Histidine decarboxylase activity
  • unchanged in
    • Posterior hypothalamus of young and adult SHR
    • Medulla oblongata of young and adult SHR
    • Anterior hypothalamus of young SHR mice
    • The cortex, midbrain, and brainstem of adult SHR (but higher than in young SHR and WKY)
  • slightly elevated
    • Anterior hypothalamus of adult SHR mice
  • increased
    • in the midbrain cortex of young and adult SHR
• Histamine N-methyltransferase
  • increased
    • in the midbrain cortex of young SHR mice
  • reduced
    • in the midbrain cortex of adult SHR mice
• H3 receptor¹⁴⁶
  • reduced number of amplicons
  • increasing H3 receptor density in the cortex with age, accompanied by a decrease in the number of expressed amplicons
  • Despite the decrease in the number of H3 receptor amplicons expressed, expression of the larger amplicon (~500 bp) increased

Depletion of histamine in young SHR rats resulted in a delay in the age-related rise in blood pressure.¹⁴⁷
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 urinary norepinephrine levels typical of SHR.¹⁴³
Histamine appears to lower blood pressure in SHR by inhibiting sympathetic activity via the central histamine H3 receptor. The blood pressure-lowering 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 ultimately increase histamine levels) significantly and in a dose-dependent manner improved the learning performance of SHR pups, as did methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (an agonist at nicotinic acetylcholine receptors, 0.03 mg/kg s.c.). The H3R agonist (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the cognitive-enhancing effects of ciproxifan.¹²⁹

In SHR, the histamine doses that increase the permeability of the blood-brain barrier vary up or down.¹⁴⁸

9.5. Almost all ADHD medications increase histamine levels¶

Only viloxazine appears not to increase histamine levels and to have little effect on the histamine system.¹⁴⁹

Since ADHD medications—and stimulants in particular—increase histamine levels only in the brain but reduce them in the rest of the body, they should generally be beneficial for people with histamine intolerance (which affects the gut peripherally rather than centrally).

9.5.1. ADHD Medications and Histamine in the Brain (Central)¶

All common ADHD medications increase histamine levels in the brain.
Atomoxetine and methylphenidate increased histamine levels in the PFC of rats.¹⁵⁰
Chronic administration of psychostimulants increases histamine release in the striatum.¹⁵¹
Lisdexamfetamine increases histamine levels in the PFC and hippocampus.¹⁵²

In the rat PFC, both methylphenidate and atomoxetine, at a dose of 1 mg/kg, significantly increased extracellular histamine levels. It has been suggested that the increased histamine release in the PFC could be an additional mechanism of action of ADHD medications. Histaminergic pathways from the tuberomammillary nucleus increase, among other things, acetylcholine release in the PFC. In a comparative study, methylphenidate (3 mg/kg) increased motor activity to the same extent as modafinil, without increasing histamine release in the anterior hypothalamus. Histaminergic involvement is thus region-specific and does not contribute to all stimulant effects.¹⁵³ Even the mere injection of the vehicle solution produced a temporary twofold increase in histamine as a consequence of handling and injection stress. The effect of the active ingredients was tested against this control condition and was significant; however, the study does not allow for conclusions regarding dose-dependence or transferability to humans. Measurements were taken exclusively in the PFC, not in the rest of the body. No conclusions can be drawn from this regarding skin reactions, mucosal swelling, or other symptoms typically associated with histamine. All four authors were employed by Pfizer Global Research and Development, which at the time was developing histamine H3 receptor antagonists for the treatment of ADHD.

9.5.2. ADHD Medications and Histamine in the Body (Peripheral)¶

Lisdexamfetamine reduced histamine levels by strongly upregulating DAO, which promotes histamine degradation.¹⁵⁴

For more information, see Histamine Intolerance / Mast Cell Activation Syndrome in the article Choosing Medications for ADHD or ADHD with Comorbidities

We’re thinking about:
Since hypothalamic neuronal histamine (as well as glucagon-like peptide-1 (GLP-1) and corticotropin-releasing hormone (CRH)) suppress food intake¹⁵⁵, the increase in histamine mediated by ADHD medications—provided it also occurs in the hypothalamus—could be a pathway that mediates the well-known appetite-suppressing effect of stimulants.

9.6. H2R deficiency can cause ADHD symptoms¶

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

• weakens the neural 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 plays a role in regulating the HPA axis during stressful situations.¹⁵⁶³⁶
Histamine release is a sensitive indicator of stress. Immobilization stress and cold reduce histamine¹⁵⁷ and histamine turnover, respectively.¹⁵⁸ Short-term stress (5 minutes) reduces histamine in the midbrain, whereas longer-lasting stress (30 to 60 minutes) or repeated stress (15-minute intervals) does not.¹⁵⁹ Exposing rats to air blasts for 1, 5, and 15 minutes increased histamine levels in the hypothalamus. Histamine levels in the midbrain were elevated after 1 and 5 minutes of exposure, while histamine levels in the cerebral cortex rose only after 1 minute of exposure. Prolonged stress (30 minutes) did not affect histamine concentration in the three brain regions studied, although plasma corticosterone levels remained very significantly elevated (14.5-fold). Repeated exposure of rats to 15-minute bursts of air led to a significant increase in histamine concentration in the hypothalamus, while histamine levels in the midbrain and cerebral cortex were not significantly altered.¹⁶⁰
In awake rats (12 months old), 15 minutes of stress increased histamine levels in the hypothalamus, but not in the cortex or midbrain.¹⁶¹
Acute stress increased histamine turnover in the diencephalon, the nucleus accumbens, and the striatum. Chronic immobilization stress increased histamine turnover in the nucleus accumbens and the striatum, but not in the diencephalon.¹⁵¹
Rats have five distinct groups of histamine neurons (E1–E5) in the tuberomammillary nucleus (TMN) in the posterior hypothalamus. Immobilization stress, insulin-induced hypoglycemia, and foot shock specifically 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 in the histaminergic groups E1, E2, and E3. Ether stress, acute hyperosmotic stimulation, or the injection of bacterial lipopolysaccharide did not activate the hypothalamic histamine neurons.¹⁵⁶

TMN neurons can integrate various stress signals (endocrine signals, external stimuli, body awareness).¹⁵⁵
Stress triggers the neuroendocrine release of ACTH, beta-endorphin, and AVP from the pituitary gland via histamine.¹⁶²

A central injection of CRH increased histamine turnover. CRH-1 receptors are located on the cell bodies of histamine neurons.¹⁵⁵

Histamine injections into the PVN activate the HPA axis through the release of CRH. During systemic stress, histamine and CRH are released from mast cells in the leptomeninges and along the cerebral capillaries
are released and regulate the permeability of the blood-brain barrier in response to stress.¹⁶³