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Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an
organic chemical In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
closely related to
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
, and synthesized biologically by a homologous pathway. Octopamine is often considered the major "fight-or-flight" neurohormone of invertebrates. Its name is derived from the fact that it was first identified in the salivary glands of the octopus. In many types of invertebrates octopamine is an important neurotransmitter and
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
. In
protostome Protostomia () is the clade of animals once thought to be characterized by the formation of the organism's mouth before its anus during embryogenesis, embryonic development. This nature has since been discovered to be extremely variable among Pro ...
s — arthropods, molluscs, and several types of worms — it substitutes for norephinephrine and performs functions apparently similar to those of norepinephrine in mammals, functions that have been described as mobilizing the body and nervous system for action. In mammals octopamine is found only in trace amounts, and no biological function has been solidly established for it. It is also found naturally in numerous plants, including
bitter orange Bitter orange, Seville orange, bigarade orange, or marmalade orange is the citrus tree ''Citrus'' × ''aurantium'' and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of the world. It is probably a cross be ...
. Octopamine has been sold under trade names such as Epirenor, Norden, and Norfen for use as a
sympathomimetic drug Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart ...
, available by prescription.


Functions


Cellular effects

Octopamine exerts its effects by binding to and activating receptors located on the surface of cells. These receptors have mainly been studied in insects, where they can be divided into distinct types: # OctαR ( alpha-adrenergic-like), are structurally and functionally similar to noradrenergic alpha-1 receptors in mammals. There are multiple subtypes of the OctαR receptor. For example, the kissing bug (''
Rhodnius prolixus ''Rhodnius prolixus'' is the principal triatomine vector of the Chagas parasite due to both its sylvatic and domestic populations in northern South America as well as to its exclusively domestic populations in Central America. It has a wide ran ...
'') has Octα1-R, Octα2R. # OctβR (
beta-adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine in ...
-like), are structurally and functionally similar to noradrenergic beta receptors in mammals. There are multiple subtypes of the OctβR receptor. For example, the fruit fly (''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'') has DmOctβ1R, DmOctβ2R, and DmOctβ3R. # OAMB. The diversity of this receptor is relatively unknown. The fruit fly (Drosophila melanogaster) has two distinct isoforms which are functionally distinct: OambK3 and OambAS. # TyrR (mixed octopamine/tyramine receptors), which are structurally and functionally similar to noradrenergic alpha-2 receptors in mammals. Receptors in the TyrR class, however, are generally more strongly activated by
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood ...
than by octopamine. Phylogenetic studies claim that in ancient
bilaterians The Bilateria or bilaterians are animals with bilateral symmetry as an embryo, i.e. having a left and a right side that are mirror images of each other. This also means they have a head and a tail (anterior-posterior axis) as well as a belly and ...
such as
Platynereis dumerilii ''Platynereis dumerilii'' is a species of annelid polychaete worm. It was originally placed into the genus ''Nereis'' and later reassigned to the genus '' Platynereis''. ''Platynereis dumerilii'' lives in coastal marine waters from temperate t ...
there is a co-existence of
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
,
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood ...
and octopamine receptor signaling. However, due to partial overlapping in their signalling functionality tyramine and octopamine receptors have been lost in vertebrates. In vertebrates no octopamine-specific receptors have been identified. Octopamine binds weakly to receptors for
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
and epinephrine, but it is not clear whether this has any functional significance. It binds more strongly to
trace amine-associated receptor Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...
s (TAARs), especially
TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...
.


Invertebrates

Octopamine was first discovered by Italian scientist
Vittorio Erspamer Vittorio Erspamer (30 July 1909 – 25 October 1999) was an Italian pharmacologist and chemist, known for the identification, synthesis and pharmacological studies of more than sixty new chemical compounds, most notably serotonin and octopamine. ...
in 1948 in the salivary glands of the octopus and has since been found to act as a neurotransmitter,
neurohormone A neurohormone is any hormone produced and released by neuroendocrine cells (also called neurosecretory cells) into the blood. By definition of being hormones, they are secreted into the circulation for systemic effect, but they can also have a role ...
and
neuromodulator Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...
in
invertebrate Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
s. Although Erspamer discovered its natural occurrence and named it, octopamine had actually existed for many years as a pharmaceutical product. It is widely used in energy-demanding behaviors by all insects, crustaceans (crabs, lobsters, crayfish), and spiders. Such behaviors include modulating muscle tension, flying, ovulation and egg-laying, and jumping.


''Octopamine in non-insect invertebrates''

In lobsters, octopamine seems to direct and coordinate
neurohormone A neurohormone is any hormone produced and released by neuroendocrine cells (also called neurosecretory cells) into the blood. By definition of being hormones, they are secreted into the circulation for systemic effect, but they can also have a role ...
s to some extent in the central nervous system, and it was observed that injecting octopamine into a lobster and crayfish resulted in limb and abdomen extension. In the nematode, octopamine is found in high concentrations in adults, decreasing egg-laying and pharyngeal pumping behaviors with an antagonistic effect to serotonin. Octopaminergic nerves in the mollusc may be present in the heart, with high concentrations in the nervous system. In larvae of the oriental armyworm, octopamine is immunologically beneficial, increasing survival rates in high-density populations.


''Octopamine in non-Drosophila insects''

In insects, octopamine is released by a select number of neurons, but acts broadly throughout the central brain, on all sense organs, and on several non-neuronal tissues. In the thoracic ganglia, octopamine is primarily released by DUM (dorsal unpaired median) and VUM (ventral unpaired median) neurons, which release octopamine onto neural, muscular, and peripheral targets. These neurons are important for mediating energy-demanding motor behaviors, such as escape-induced jumping and flight. For example, the locust DUMeti neuron releases octopamine onto the extensor tibia muscle to increase muscle tension and increase relaxation rate. These actions promote efficient leg muscle contraction for jumping. During flight, DUM neurons are also active and release octopamine throughout the body to synchronize energy metabolism, respiration, muscle activity and flight interneuron activity. Octopamine in locusts is four times more concentrated in the axon than in the soma, and decreases the locust's myogenic rhythm. In the
honey bee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current cosm ...
, octopamine has a major role in learning and memory. In the firefly, octopamine release leads to light production in the lantern. The
emerald cockroach wasp The emerald cockroach wasp or jewel wasp (''Ampulex compressa'') is a solitary wasp of the family Ampulicidae. It is known for its unusual reproductive behavior, which involves stinging a cockroach and using it as a host for its larvae. It thus ...
stings the host for its larvae (a cockroach) in the head ganglion (brain). The venom blocks octopamine receptors and the cockroach fails to show normal escape responses, grooming itself excessively. It becomes docile and the wasp leads it to the wasp's den by pulling its antenna like a leash.


''Octopamine in Drosophila''

Octopamine affects almost every process of the fruit fly and is widely present in both the adult and larval fly. A non-exhaustive list of some of the areas in which Octopamine modulates: * Learning and memory * Ovulation and Egg-Laying * Locomotion * Muscle Physiology * Aggression * Alcohol and drug tolerance * Feeding * Microbiome and gut physiology * Sleep * Modulating effects of exercise * Metabolism


Vertebrates

In
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
s, octopamine replaces
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
in sympathetic
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s with chronic use of monoamine oxidase inhibitors. It may be responsible for the common
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
of
orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...
with these agents, though there is also evidence that it is actually mediated by increased levels of ''N''-acetylserotonin. One study noted that octopamine might be an important amine that influences the therapeutic effects of inhibitors such as monoamine oxidase inhibitors, especially because a large increase in octopamine levels was observed when animals were treated with this inhibitor. Octopamine was positively identified in the urine samples of mammals such as humans, rats, and rabbits treated with monoamine oxidase inhibitors. Very small amounts of octopamine were also found in certain animal tissues. It was observed that within a rabbit's body, the heart and kidney held the highest concentrations of octopamine. Octopamine was found to be 93% eluted by urine within 24 hours of being produced in the body as a byproduct of Iproniazid in rabbits.


Pharmacology

Octopamine has been sold under trade names such as Epirenor, Norden, and Norfen for use in medicine as a
sympathomimetic drug Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart ...
, available by prescription. Very little information exists concerning its clinical usefulness or safety, though. In mammals, octopamine may mobilize the release of
fat In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food. The term often refers specifically to triglycerides (triple est ...
from
adipocytes Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
(fat cells), which has led to its promotion on the
internet The Internet (or internet) is the global system of interconnected computer networks that uses the Internet protocol suite (TCP/IP) to communicate between networks and devices. It is a '' network of networks'' that consists of private, pub ...
as a slimming aid. However, the released fat is likely to be promptly taken up into other cells, and there is no evidence that octopamine facilitates weight loss. Octopamine may also increase blood pressure significantly when combined with other stimulants, as in some weight loss supplements. Th
World Anti-Doping Agency
lists octopamine as a banned substance for in competition use, as a "specified stimulant" on the 2019 Prohibited List.


Insecticides

The octopamine receptor is a target of insecticides, as its blockage leads to decreased cAMP levels. Essential oils can have such a neuro-insecticidal effect, and this octopamine-receptor mechanism is naturally utilized by plants with active insecticidal phytochemicals.


Biochemical mechanisms


Mammals

Octopamine is one of four primary
endogenous agonist In pharmacology, an endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. For example, the primary endogenous agonist for serotonin receptors is serotonin, and the ...
s of human
trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...
together with 3-iodothyronamine, dopamine and
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood ...
.


Invertebrates

Octopamine binds to its respective G-protein coupled receptors (GPCRs) to initiate a cell signal transduction pathway. At least three groups of octopamine GPCR have been defined. OctαR (OCTOPAMINE1 receptors) are more closely related to α-adrenergic receptors, while OctβR (OCTOPAMINE2 receptors) are more closely related to β-adrenergic receptors. The Octopamine/Tyramine receptors (including Oct-TyrR) can bind both ligands, and display agonist-specific coupling. Oct-TyrR is listed in both OCTOPAMINE and TYRAMINE RECEPTORS gene groups.


Biosynthesis


In insects

Octopamine acts as the
insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three ...
equivalent of
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
and has been implicated in regulating aggression in invertebrates, with different effects on different species. Studies have shown that reducing the neurotransmitter octopamine and preventing coding of tyramine beta hydroxylase (an enzyme that converts
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood ...
to octopamine) decreases aggression in ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'' without influencing other behaviors.


In humans


See also

* Phenethylamine * Phenylethanolamine *
Trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to th ...


References

{{Phenethylamines Alpha-1 adrenergic receptor agonists Norepinephrine-dopamine releasing agents Phenols TAAR1 agonists Trace amines Phenylethanolamines Neurotransmitters Phenethylamines