Tyramine is a
norepinephrine and dopamine releasing agent (NDRA) and indirectly acting
sympathomimetic. Additionally, the possibility that tyramine acts directly as a
neuromodulator was revealed by the discovery of a
G protein-coupled receptor with high
affinity for tyramine, called the
trace amine-associated receptor (TAAR1). The TAAR1 receptor is found in the
brain, as well as peripheral tissues, including the
kidneys. Tyramine is a
full agonist of the TAAR1 in rodents and humans. Tyramine is physiologically metabolized by
monoamine oxidases (primarily
MAO-A),
FMO3,
PNMT,
DBH, and
CYP2D6. If monoamine metabolism is compromised by the use of
monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a
hypertensive crisis can result, as tyramine also can displace stored monoamines, such as
dopamine,
norepinephrine, and
epinephrine, from pre-
synaptic vesicles. Tyramine is considered a "
false neurotransmitter", as it enters noradrenergic nerve terminals and displaces large amounts of norepinephrine, which enters the blood stream and causes vasoconstriction. Additionally, cocaine has been found to block blood pressure rise that is originally attributed to tyramine, which is explained by the blocking of
adrenaline by cocaine from reabsorption to the brain. The first signs of this effect were discovered by a British pharmacist who noticed that his wife, who at the time was on MAOI medication, had severe headaches when eating cheese. For this reason, it is still called the "cheese reaction" or "cheese crisis", although other foods can cause the same problem. Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as
Stilton) do. A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in
systolic blood pressure of 30
mmHg or more. The increased release of norepinephrine (noradrenaline) from neuronal cytosol or storage vesicles is thought to cause the
vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases,
adrenergic crisis can occur. Although the mechanism is unclear, tyramine ingestion also triggers migraine attacks in sensitive individuals and can even lead to stroke. Vasodilation, dopamine, and circulatory factors are all implicated in the migraines. Double-blind trials suggest that the effects of tyramine on migraine may be
adrenergic. Research reveals a possible link between
migraines and elevated levels of tyramine. A 2007 review published in Neurological Sciences presented data showing migraine and cluster diseases are characterized by an increase of circulating neurotransmitters and
neuromodulators (including tyramine,
octopamine, and
synephrine) in the hypothalamus, amygdala, and dopaminergic system. People with migraine are over-represented among those with inadequate natural monoamine oxidase, resulting in similar problems to individuals taking MAO inhibitors. Many migraine attack triggers are high in tyramine. If one has had repeated exposure to tyramine, however, there is a decreased pressor response; tyramine is degraded to octopamine, which is subsequently packaged in synaptic vesicles with norepinephrine (noradrenaline). Therefore, after repeated tyramine exposure, these vesicles contain an increased amount of octopamine and a relatively reduced amount of norepinephrine. When these vesicles are secreted upon tyramine ingestion, there is a decreased pressor response, as less norepinephrine is secreted into the
synapse, and octopamine does not activate alpha or beta
adrenergic receptors. When using a MAO inhibitor (MAOI), an intake of approximately 10 to 25 mg of tyramine is required for a severe reaction, compared to 6 to 10 mg for a mild reaction. Tyramine, like
phenethylamine, is a
monoaminergic activity enhancer (MAE) of
serotonin,
norepinephrine, and
dopamine in addition to its catecholamine-releasing activity. That is, it enhances the
action potential-mediated release of these
monoamine neurotransmitters. When given via
intracerebroventricular injection in rodents pre-treated with
monoamine oxidase inhibitors (MAOIs), tyramine has been found to induce the
head-twitch response in rodents. This effect appears to be mediated by induction of
serotonin release. ==Biosynthesis==