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.