Histamine's effects

Technical Bulletin - Issue 11 - Histamine July 28, 2004 Issue 11 Editor: Gottfried Kellermann, PhD Contributors for this issue: Mike Bull Joe Ailts Carol Arndt, Bill Wilson, M.D. The Technical Support staff at NeuroScience is proud to bring you another informative newsletter designed to keep you up to date with current developments taking place within our company. Here you will find product reviews, new test parameter announcements, neurotransmitter interpretation suggestions, and anything else relevant to the world of neurotransmitters. The NeuroScience Technical support staff has revised its Technical Guide which reviews of many of the aspects of neurotransmitter testing and amino acid therapy. NeuroScience has a New Website. Please take a moment to visit and review the new information and the new format. Our tenth newsletter reviewed the new biphasic approach to TAAT (Targeted Amino Acid Therapy) that is more effective for patients with fatigue and relevant to this newsletter, increases histamine. Here, in our eleventh issue, we will focus on the neurotransmitter, histamine, a relatively new addition to the NeuroScience testing menu. Feel free to send us your questions and comments to be addressed in this newsletter. Your input is appreciated! Histamine is a recent addition to the NeuroScience testing menu and is now being measured routinely. Research by NeuroScience in the development of assays for neurotransmitters has created this new cost-effective assay and histamine now joins GABA and PEA in our expanding test menu. (A neurotransmitter test for glutamate and a test for the amino acid glutamine have also been developed and are available in the panel listed below. They will be the subject of an upcoming Technical Bulletin.) The actions of histamine are very well-known in the immune system. However, the actions of histamine within the central nervous system (CNS) are less familiar. Immunologically, histamine is released from mast cells or formed via histidine decarboxylase an enzyme that is up regulated in response to inflammatory cytokines. It is the presence of the immune response that triggers the increase in histamine that revs up mucus production to incredible levels and causes runny noses and hacking coughs. Without the immunological assault, e.g. increased cytokines, allergens, or IgE, histamine is a mild-mannered hardworking Clark Kent. Histamine is a neurotransmitter and histamine containing neurons have been found to have a pacemaker function within the brain. The firing rate of these neurons correlate positively with brain activity levels and display distinct day-night rhythms. Within the posterior region of the hypothalamus there are a large number of neurons that synthesize and utilize histamine and these neurons provide the stimulation that maintains or modulates activity in many other regions of the brain. Histamine, like the other biogenic amines (serotonin, dopamine, norepinephrine, epinephrine, and PEA) is stored in presynaptic vesicles and is released into the synapse. Also like other amine neurotransmitters, histamine binds to transmembrane G-protein coupled receptors on the post-synaptic neurons to exert its function. Histamine crosses the blood-brain-barrier very poorly and is synthesized within histamine neurons via the decarboxylation of histidine. Histidine is an essential amino acid and readily crosses the blood-brain-barrier via the LNAAT (large neutral amino acid transporter). The histidine decarboxylase enzyme is not rate-limiting and increasing the availability of histidine will increase the synthesis of histamine. Unlike other monoamines, histamine does not appear to have a specific reuptake mechanism for inactivation. Instead, histamine is inactivated by the ubiquitously present histamine methyltransferase and subsequent deamination by monoamine oxidase B. Some of the effects of histamines are best known because of the effects of antihistamine medications. First generation antihistamines are an excellent example. These medications block (antagonize) the actions of histamine by binding to the histamine receptor and as such prevent histamine from gaining access. First generation antihistamines, by definition, cross the blood-brain-barrier and interact with histamine receptors in the periphery as well as the CNS. Typical examples are: Diphenhydramine (Benadryl), Carbinoxamine (Clistin), Clemastine (Tavist), Chlorpheniramine (Chlor-Trimeton), and Brompheniramine (Dimetane). First generation antihistamines are also associated with significant drowsiness and diphenhydramine is included in OTC sleep aids (Unisom, Sominex, Nytol, etc.), because of this effect. Second generation or the so-called "non-drowsy" antihistamines, in contrast, do not cross the blood-brain barrier. So, while second generation antihistamines block the same receptors, they do not interact with those in the brain and therefore do not block the excitatory activity of histamine. Common examples are: Fexofenadine (Allegra), Loratidine (Claritin), Cetirizine (Zyrtec), and Acrivastine (Semprex). The excitatory action of histamine agrees very well with the observed activity of histamine neurons, which are active during the day, less active at night, and almost completely inactive during REM sleep. There are at least four types of histamine receptors (H1...H4) numbered according to their order of discovery. H1 H1 receptors are located in the periphery in the smooth muscles of intestines, bronchi, and blood vessels, as well as the CNS and are the main target for the antihistamine medications used to address allergies and the immune response. H1 receptors within the central nervous system are also responsible for the stimulatory properties of histamine and the improvement in cognitive function, vigilance, and memory caused by histamine. H2 H2 receptors on neurons are primarily post-synaptically located and receptors are coupled to adenylyl cyclase and increase cAMP for energy production. High densities of H2 receptors are found within the CNS. Activation of these receptors has primarily an excitatory effect on neurotransmission via alterations in ion channel activity that favor neuron depolarization. The H2 receptors are also present in the periphery, including the gastric mucosa, immune cells, and myocytes. Drugs acting on the H2 receptors in the gut prevent histamine from stimulating the secretion of gastric acid and have been widely prescribed for the treatment of gastro-esophageal reflux and peptic ulcer disease. In general, H2 receptor blockers do not cross the blood-brain barrier. Common examples are: Cimetidine (Tagamet), Ranitidine (Zantac), Famotidine (Pepcid), Nizatidine (Axid). In patients with poor digestion increasing gastric acid production by increasing histamine can aid digestion by stimulating acid secretion. H3 H3 are believed to be auto-receptors that act to down-regulate histamine release and synthesis and thereby reduce the effects of H1 and H2 receptors. However the greatest concentration of H3 receptors exist in areas of the brain that have more non-histamine neurons. As such, histamine release, acting via the H3 receptor, can modulate the activity of serotonin and dopamine neurons as well. Behavioral animal studies have shown that enhancing the actions of histamine, through the use of H3 receptor blockers, causes significant improvements in memory and learning. H4 H4 receptors have only recently been discovered and seem in some ways to act like H3 receptors but are located in mast cells as well as in the CNS. They seem to increase calcium mobilization from intracellular calcium stores. Histidine is important in a number of biological functions. The imidazole ring of histidine allows it to act as either an acid or base at physiological pH. Because of this, histidine can catalyze many chemical reactions and is found in the reactive center of many enzymes. Similarly, it is the ability of histidine molecules in hemoglobin to buffer H+ ions in red blood cells that allows for the exchange of O2 and CO2 at the tissues or lungs, respectively. Histidine has also been found to have anticonvulsant properties. Animal models of epilepsy report that histidine will decrease the incidence of seizures. Supporting the importance of histamine are studies which find that histamine blockers can reduce the effectiveness if some antiseizure medication. Many supplements tout histidine supplementation as a way to increase sexual pleasure and orgasm intensity. We are not aware of any research published to support this claim. Permitting a few degrees of separation, histidine, which increases histamine, can increase the release of oxytocin, which is a neuropeptide that is also associated with orgasms. So, a theoretical link is possible. Please send us an email if you have any comments about this. Observations by NeuroScience regarding the use of histidine come from the product ExcitaCor. ExcitaCor and TravaCor have been used in therapy regimens for patients presenting with neurotransmitter deficiencies in epinephrine and dopamine and is chosen over other therapies specifically when these values are accompanied by complaints of fatigue. Details of this protocol were outlined in our tenth Technical Bulletin. We have seen through neurotransmitter testing that ExcitaCor, a histidine containing product will increase histamine levels. Subjects taking histidine containing therapies reported feeling less fatigued and more alert. No allergy symptoms were observed. Neurotransmitter tests in these studies also confirm that the histidine in ExcitaCor will, via the neuromodulatory role of histamine, increase the release of the catecholamines: epinephrine and norepinephrine. We have also seen that young patients with autism or ADHD have higher histamine levels. This could be a contributing factor in the hyperkinetic facet of ADHD as well as an influence in the clinical presentation of the autism patient. We have also observed that high histamine levels are reduced when TAAT products that increase serotonin are used and recommend increasing serotonin when histamine is high. Even if serotonin levels are not low. This is beneficial in two ways. First patients with high histamine levels are more likely to to have an excess of stimulatory neurotransmitter activity and increasing serotonin will minimize that excess. Second, increasing serotonin can reduce allergy symptoms. This has been reported by practitioners using NeuroScience products with their patients as well as in published reports of antidepressants being used in dermatology to eliminate skin rashes. It has been reported that patients with depression have histamine receptors that don't bind histamine as well as the receptors of non-depressed subjects. This reduced function may be overcome by increasing histamine levels. Our observations show that patients suffering from depression have lower histamine levels. * Histamine is an excitatory neurotransmitter * Histamine acts as a pacemaker to increase activity in many regions of the brain * Histamine increases the release of epinephrine and norepinephrine * Supplementation with histidine contributes to the modulation of fatigue and depression. * Neurotransmitter testing data shows that ExcitaCor will increase histamine * High histamine can be reduced by increasing serotonin The mechanism of spontaneous firing in histamine neurons. Stevens DR, Eriksson KS, Brown RE, Haas HL. Behav Brain Res. 2001 Oct 15;124(2):105-12. Review. The physiology of brain histamine. Brown RE, Stevens DR, Haas HL.Prog Neurobiol. 2001 Apr;63(6):637-72. Review. Importance of histamine in modulatory processes, locomotion and memory. Philippu A, Prast H. Behav Brain Res. 2001 Oct 15;124(2):151-9. Review Histidine induces lipolysis through sympathetic nerve in white adipose tissue. Yoshimatsu H, Tsuda K, Niijima A, Tatsukawa M, Chiba S, Sakata T. Eur J Clin Invest. 2002 Apr;32(4):236-41. Central histaminergic system and cognition. Passani MB, Bacciottini L, Mannaioni PF, Blandina P. Neurosci Biobehav Rev. 2000 Jan;24(1):107-13. Review. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS. J Neurosci. 2002 Sep 1;22(17):7695-711. Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. John J, Wu MF, Boehmer LN, Siegel JM.Neuron. 2004 May 27;42(4):619-34. Histamine activates tyrosine hydroxylase in bovine adrenal chromaffin cells through a pathway that involves ERK1/2 but not p38 or JNK. Cammarota M, Bevilaqua LR, Rostas JA, Dunkley PR. J Neurochem. 2003 Feb;84(3):453-8. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP. J Pharmacol Exp Ther. 2003 Jun;305(3):1212-21. Epub 2003 Mar 06. L-histidine is a beneficial adjuvant for antiepileptic drugs against maximal electroshock-induced seizures in mice. Kaminski RM, Zolkowska D, Kozicka M, Kleinrok Z, Czuczwar SJ. Amino Acids. 2004 Feb;26(1):85-9. Epub 2003 May 09. Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice. Masaki T, Chiba S, Yoshimichi G, Yasuda T, Noguchi H, Kakuma T, Sakata T, Yoshimatsu H. Endocrinology. 2003 Jun;144(6):2741-8. Histamine and prostaglandin interaction in regulation of oxytocin and vasopressin secretion. Knigge U, Kjaer A, Kristoffersen U, Madsen K, Toftegaard C, Jorgensen H, Warberg J.J Neuroendocrinol. 2003 Oct;15(10):940-5. Subcellular distribution of histamine, GABA and galanin in tuberomamillary neurons in vitro. Kukko-Lukjanov TK, Panula P.J Chem Neuroanat. 2003 Jul;25(4):279-92. The role of central histaminergic neuron system as an anticonvulsive mechanism in developing brain. Yokoyama H. Brain Dev. 2001 Nov;23(7):542-7. Review. The use of antidepressant drugs in dermatology. Gupta MA, Guptat AK. J Eur Acad Dermatol Venereol. 2001 Nov;15(6):512-8. Review. We hope you enjoyed this edition of The NeuroScience Technical Bulletin. Copyright 2003, 2004 by NeuroScience, Inc. 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