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Sunday, August 31, 2014

Histamine Receptors H1,H2,H3 and Neurotransmitter / Hormone Release

Histamine H(1) Receptor Activation 

ACTIONS when Activated
  • Potentiate and Activate GABA release (1) - is Ca2+ dependent.
  • Inhibit or Stimulate Noradrenaline Activity, enhances norepinephrine and glutamate especially when H(3)'s are blocked. (2) (3) (4)
  • Inhibit Potassium-evoked serotonin release. (5)
  • Increases phospholipase C and PKC (Protein Kinase C)-induced NT release. (6)
  • Increases tyrosine hydroxylase (and thus production of dopamine from tyrosine). (7)
  • Increases cortisol, ACTH, beta-endorphin and Prolactin release. (8) (9) (10)
  • Increases neuronal nNOS, iNOS and eNOS (nitric oxide synthases, increases N.O) (11)
  • Nitric Oxide is partly increased by histamine through Ca2+, although other channels may be involved as well.
  • Upregulation of Alpha-Adrenergic Receptors and Activity (12)
  • Amplifies NMDA-induced depolarization. (13)
  • Induces Calcium Channel induced cAMP (cyclic adenosine monophosphate) and Cytosolic Ca2+ concentrations. (14) (15)
  • Increases and Amplifies Glutamate Release (16)
  • Increases Acetylcholine Release (17)
  • Increases GnRH (Gonadotropin-Releasing-Hormone) and thus stimulates production of sex hormones (18).
  • Inhibits growth hormone release. (19)
  • Stimulates Oxytocin Release. (20) (21)

THINGS THAT AFFECT NEGATIVELY HISTAMINE (H1) Receptor Expression and Histamine Release

  • Beta-Adrenergic Agonists (such as albuterol, clenbuterol and higenamine will decrease H(1) receptor mRNA with time. (!)
  • Sensitive to some antipsychotics and may downregulate in response to high potency blockade, however there are some studies indicate it can elicit supersensitivity and become immune to blockade.

  • High Levels of Adrenaline or use of adrenergic analogs aside from beta-agonists. Alpha-2-Receptor activation inhibits histamine release. (!) (!) (!) (!) (!) (!)
  •  High Copper levels (also increases histamine breakdown through Diamine Oxidase. (!)
  • Serotonin 5-HT1A (presumably post-synaptic) activation. (!) (!)
  • Corticotropin-Releasing Hormone and Cortisol decrease histamine synthase enzymes (!)
  • Use of Green Tea; catechin supplements and naringenin may decrease histamine synthesis and correspondingly, H(1) receptor mRNA. (!)
  • Low Estrogen Levels. (!)

WHAT UPREGULATES H(1) Receptors Expression and Histamine Activity

  • Protein Kinase C activation (such as with alpha-1-agonists or 5-HT2A agonism seen with LSD) (!) 
  • H(3)R blockade by betahistine, thioperamide, Clobenpropit etc (!) (!)
  • Alpha-2-Blockade and Low Serotonin Levels. (!) (!) (!)
  • Estradiol (Estrogen) (!) (!) (!)
  • Complex; but NMDA-blockade enhances histamine release, yet indirect upregulation of aromatase activity by NMDA may then lead to histamine release. (!) (!)
  • 5-HT1A blockade.(!)
  • High Protein Diet (!) (!) (!)
  • Muscarinic Receptor Activation and anything that decreases Cyclic AMP (beta blockers etc) (!) (!)
  • Some central nicotinic receptors and thus nicotine use (affects HDC) (!) (!)
  • Dopamine D(2) Agonists (parkinson's drugs; requip and pramipexole mainly)

                            HISTAMINE H(2) Receptor Activation
                              Actions when Activated

  • Increases glycine activity as well as Ca2+ stimulated influx of glutamate release. (!)
  • Stimulates hypothalamic norepinephrine (noradrenaline) levels. (!)
  • Increases Acetylcholine (striatal) when stimulated on Cholinergic/GABAergic neurons. (!) (!) (!)
  • H(2) Receptors are found co-localized with norepinephrinergic nerve terminals, as well as dopamine expressing neurons and GABAergic terminals. Each area will yield a different result, thus it is difficult to say in ratio what H(2) receptor activation would, given unique circumstances and brain development. (!) (!)
  • Potently increases cAMP levels (cyclic AMP) - is even more potent than Beta-Adrenergic Activation in this regard. (!) (!)  
  • Increases Gonadotropins; Testosterone,Estradiol by this same mechanism.
  • Increases T4 Converstion from TSH, increases metabolism (just as forskolin would). (!) (!)
  • Increases GABA release. (!) (!)
  • Increases Oxytocin release. (!) (!)
  • Broadly excites glutamatergic neurotransmisson (!)

                                                                   Relation to Behavior
Histamine H(2) blockade causes fear like responses and unwarranted fear behavior. It also may induce paranoia and hallucnations in vulnerable subjects. Thus, taking stomach acid pills that can cross the BBB may result in negative psychological manifestations and negative behavioral phenotypes. In addition, H2 activated-dependent cAMP produces an antipsychotic effect and may alleviate psychosis.

On the flip side, super high histamine may induce adrenal fatigue and low adrenaline levels, leading to a fearless state of mind but corresponding fatigue as well. High Histamine individuals tend to have high libido and fast sexual responsiveness as well. 

Histamine Actions in the Central Nervous System



  • Inhibit Dopamine D(1) receptor activated cAMP levels. (!)
  • Inhibit histamine release and production. (!)
  • Inhibits dopamine production. (!)
  • Downregulates/Decreases Dopamine D2 Receptors. (!)
  • Depresses synaptic transmission and CNS function. (!)
  • Inhibits norepinephrine release. (!)
  • Inhibits Dopamine D(1) stimulated GABA release. (!)
  • Inhibits Serotonin Release. (!)
  • Inhibits Glutamate Release. (!)
  • Inhibits Dopamine Synthesis (Production) (!)
  • Inhibits Acetylcholine Activity and Release. (!) (!)
  • Increases MAPK signaling. (!) (!)
  • Increases Growth Hormone. (!)


                      Histamine Receptors in Human Prefrontal Cortex

                            HISTAMINE AND EMOTIONAL MEMORY

 Decreased Histamine Release / Histamine Deficient Mice causes Anxiety-like behavior by actions in Amygdala.

      AMYGDALA KINDLING IN H(1) Receptor Deficient Mice

                                            Histamine receptors influence blood-spinal cord barrier permeability, edema formation, and spinal cord blood flow following trauma to the rat spinal cord.

   Histamine H(1) Receptors and Depression::Decreased histamine H1 receptor binding in the brain of depressed patients.

Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

                                   HISTAMINE : Biology 307: Immunology

A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas.

Signal transduction by histamine in the cerebellum and its modulation by N-methyltransferase.

Cerebellar histamine-H1 receptor distribution: an autoradiographic study of Purkinje cell degeneration, staggerer, weaver and reeler mutant mouse strains. (!)

1 comment:

  1. Protopine has been found to inhibit histamine H1 receptors.


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