dopamine

Interplay between mast cells and hormones: Part 3 of 8

by Lisa Klimas
July 3, 2016July 16, 2016

Hormone	Location released	Major functions	Interaction with mast cells	Reference
Dopamine	Hypothalamus Adrenal gland (medulla)	Inhibit prolactin released from pituitary Increase heart rate and blood pressure Inhibit norepinephrine release	Enhances mast cell degranulation Perpetuates immediate and late phase hypersensitivity reactions H3 receptor activation inhibits dopamine production Dopamine is released by mast cells H1 inverse agonists increase dopamine release Histamine increases dopamine release	Mori T, et al. D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells. Journal of Dermatological Science 2013: 71, 37-44. Xue L, et al. The effects of D3R on TLR4 signaling involved in the regulation of METH-mediated mast cell activation. International Immunopharmacology 2016: 36. 187-198.
Endothelin	Stomach	Promotes smooth muscle contraction of stomach Very potent vasoconstrictor	Activates mucosal mast cells Mast cells regulate endothelin levels to prevent loss of blood flow to tissues	Boros M, et al. Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors. Clin Sci (Lond) 2007: 103(48), 31S-34S. Hultner L, Ehrenreich H. Mast cells and endothelin-1: a life-saving biological liaison. Trends Immunol 2005: 26(5), 235-238.
Epinephrine/ adrenaline	Adrenal gland (medulla), sympathetic nervous system	Fight or flight response Increases heart rate, force of heart contraction, blood pressure, energy breakdown, production of ACTH, bloodflow and energy to the brain and muscles Suppresses nonessential functions and significantly decreases GI motility and excretion of urine and stool	Epinephrine inhibits IgE mediated released of histamine, prostaglandins and TNF Epinephrine inhibits mast cell proliferation, adhesion and movement within the body SCF reduces action of epinephrine on mast cells by decreasing B2 adrenergic receptors	Cruse G, et al. Counterregulation of beta(2)-adrenoceptor function in human mast cells by stem cell factor. J Allergy Clin Immunol 2010: 125(1), 257-263. Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol 2015.
Erythropoietin	Kidney	Stimulate red blood cell production Protects nerve cells and tissues	During low oxygen events, mast cells express receptors for erythropoietin Erythropoietin can bind at the CKIT receptor Decreases inflammatory response to infection (decreases IL-6 and TNF)	Wiedenmann T, et al. Erythropoietin acts as an anti-inflammatory signal on murine mast cells. Mol Immunol 2015: 65(1), 68-76.
Estradiol and other estrogens	Ovaries, placenta, adipose tissue, testes	Drive female secondary sex characteristics Increase metabolism, uterine and endometrial growth, bone production, and the release of cholesterol in bile Increase production of proteins in liver, cortisol, sex hormone binding globulin, somatostatin, clotting factors II, VII, IX, X, antithrombin III and plasminogen, HDL, triglycerides Decrease LDL, production of adipose tissue, GI motility Modulate salt and water retention Inhibits programmed cell death of germ cells	E2 is a very potent mast cell degranulator E2 drives mast cell degranulation in ovaries to trigger ovulation Enhances IgE mediated degranulation Increased production of leukotrienes Increases mast cell density in ovaries	Zaitsu M, et al. Estradiol activates mast cells via a non-genomic estrogen receptor-a and calcium influx. Mol Immunol 2007: 44(8), 1977-1985. Zierau O, et al. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Front Immunol 2012: 3, 169.
Follicle stimulating hormone (FSH)	Pituitary	Stimulates maturation of ovarian follicles Stimulates maturation of seminiferous tubules, production of sperm and production of androgen binding protein	Triggers mast cell degranulation Increases mast cell density in ovaries	Theoharides TC, Stewart JM. Genitourinary mast cells and survival. Transl Androl Urol 2015: 4(5), 579-586. Jaiswal K, Krishna A. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Acta Physiol Hung 1996: 84(2), 183-190.
Gastric inhibitory polypeptide/ glucose-dependent insulinotropic polypeptide (GIP)	Duodenum, jejunum	Triggers release of insulin Involved in fatty acid metabolism Involved in bone formation	May suppress release of stomach acid triggered by histamine	McIntosh CHS, et al. Chapter 15 Glucose-Dependent Insulinotropic Polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitamins & Hormones 2009: 80, 409-471.
Gastrin	Stomach, duodenum, pancreas	Release of gastric acid Release of pepsinogen, the precursor to pepsin Triggers secretion of pancreatic enzyme Triggers emptying of gallbladder Increases stomach motility	Triggers release of histamine in enterochromaffin-like cells to trigger gastric acid secretion Triggers mast cell degranulation Gastrin releasing peptide, which induces gastrin release, triggers histaminergic itching response	Akiyama T, et al. Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain 2014: 155, 80-92.

Histamine effects on neurotransmitters (serotonin, dopamine and norepinephrine)

by Lisa Klimas
August 3, 2014August 16, 2017

Some of the most important actions of histamine involve regulation of neurotransmitters. Release of acetylcholine, norepinephrine and serotonin are all controlled in part by histamine levels. Injection of histamine into the hypothalamus increased metabolism of norepinephrine and serotonin, while dopamine metabolism increased in some places and not in others. Medications that block the H1 receptor increase dopamine release. Histamine stimulates prolactin release via the H2 receptor, which in turn inhibits dopamine production. Histamine can locally increase the concentration of norepinephrine.

Serotonin is a neurotransmitter. This means that cells nerve cells use this to communicate. Most of the serotonin in the body is found in the GI tract, where it controls the way the intestine moves food through it. However, one study indicated that as much as 40% of serotonin in the human body could originate in mast cells. Serotonin is metabolized to 5-HIAA, which can be tested for as a sign of mast cell activation.

Serotonin released in the GI tract eventually enters the blood stream. On its way to the blood stream, it is taken up by platelets and later used in clotting. Serotonin is released when eating, which decreases dopamine release and decreases appetite. If the food consumed is irritating to the GI tract, more serotonin is secreted to move it through the gut faster. In these situations, the serotonin cannot be fully taken up by platelets and enters the blood stream as free serotonin. When this happens, it stimulates vomiting. Some foods contain serotonin, but it does not cross the blood brain barrier and thus does not affect brain chemistry.

Mast cells contain dopamine, a hormone and neurotransmitter. This chemical is most often associated with reward seeking behavior, including addiction behaviors. It also has other important roles, including motor functions. Mast cell activation causes depletion of dopamine as frequent degranulation causes a decrease in dopamine production by these cells. Dopamine can be converted to norepinephrine.

In blood vessels, dopamine inhibits norepinephrine release and acts as vasodilator. Dopamine also increases sodium excretion and urine output, reduces insulin production, reduces GI motility, protects intestinal mucosa and reduces activity of lymphocytes. It is responsible for cognitive alertness. If you consider that high histamine levels can decrease dopamine levels, this means that in a mast cell patient, low dopamine levels might cause decreased urine output, increased GI motility and overactivation of white blood cells. Additionally, low dopamine can translate into higher than normal norepinephrine levels, which could be the link between mast cell disease and POTS. Brain fog and decreased alertness are effects of low dopamine.

Defective transmission of dopamine is also found in painful conditions like fibromyalgia and restless legs syndrome, associated with mast cell disease. Activation of D2 dopamine receptors causes nausea and vomiting. Metoclopramide is a D2 inhibitor and achieves its anti-nausea effects through this mechanism. (Note: metoclopramide can inhibit histamine metabolism and for this reason is not recommended for mast cell patients.) Some dopaminergic drugs like clozapine, bromocriptine and haloperidol inhibit mast cell degranulation.

Norepinephrine is responsible for concentration and vigilance. It also increases vascular tone by action on alpha adrenergic receptors. Norepinephrine is important in the fight or flight response, directly increasing heart rate, triggering release of glucose, increasing blood flow to skeletal muscle and increasing brain oxygen supply. Interestingly, fasting increases norepinephrine for days. Glucose intake, but not carbohydrate or protein intake, also increases norepinephrine. Increased histamine can cause increases in norepinephrine production and secretion.