In many types of invertebrates, octopamine is an importantneurotransmitter andhormone. Inprotostomes—arthropods,molluscs, and several types ofworms—it substitutes for norepinephrine 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 (i.e., it is atrace amine), and no biological function has been solidly established for it. It is also foundnaturally in numerous plants, includingbitter orange.[4][5]
Octopamine has been sold under trade names such asEpirenor,Norden, andNorfen for use as asympathomimetic drug, available by prescription.
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) has Octα1-R, Octα2R.[6]
OctβR (beta-adrenergic-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) has DmOctβ1R, DmOctβ2R, and DmOctβ3R.[7]
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.[8]
TyrR (mixed octopamine/tyramine receptors), which are structurally and functionally similar to noradrenergic alpha-2 receptors in mammals.[9] Receptors in the TyrR class, however, are generally more strongly activated bytyramine than by octopamine.[9]
Phylogenetic studies claim that in ancientbilaterians such asPlatynereis dumerilii there is a co-existence ofnorepinephrine,tyramine and octopamine receptor signaling. However, due to partial overlapping in their signalling functionality tyramine and octopamine receptors have been lost in vertebrates.[10]
In vertebrates no octopamine-specific receptors have been identified. Octopamine binds weakly to receptors fornorepinephrine andepinephrine, but it is not clear whether this has any functional significance. It binds more strongly totrace amine-associated receptors (TAARs), especiallyTAAR1.[9]
Octopamine was first discovered by Italian scientistVittorio Erspamer in 1948[11] in the salivary glands of theoctopus and has since been found to act as aneurotransmitter,neurohormone andneuromodulator ininvertebrates. Although Erspamer discovered its natural occurrence and named it, octopamine had actually existed for many years as a pharmaceutical product.[12] It is widely used in energy-demanding behaviors by all insects, crustaceans (crabs, lobsters, crayfish), and spiders. Such behaviors include modulating muscle tension,[13] flying,[14] ovulation and egg-laying,[15][16][17][18][19][20] and jumping.[21][22]
In lobsters, octopamine seems to direct and coordinateneurohormones 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.[23]
In thenematode, octopamine is found in high concentrations in adults, decreasing egg-laying and pharyngeal pumping behaviors with an antagonistic effect toserotonin.[24]
Octopaminergic nerves in themollusc may be present in the heart, with high concentrations in the nervous system.[25]
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.[26][27] 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.[28][29] 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.[26] During flight, DUM neurons are also active and release octopamine throughout the body to synchronize energy metabolism, respiration, muscle activity and flight interneuron activity.[14] Octopamine inlocusts is four times more concentrated in the axon than in the soma, and decreases the locust'smyogenic rhythm.[30]
In thehoney bee, octopamine has a major role in learning and memory. In thefirefly, octopamine release leads to light production in the lantern.[31][32]
In larvae of theoriental armyworm, octopamine is immunologically beneficial, increasing survival rates in high-density populations.[33]
Theemerald cockroach wasp stings the host for its larvae (a cockroach) in the head ganglion (brain). The venom blocks octopamine receptors[34] 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.[35]
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:
One study noted that octopamine might be an important amine that influences the therapeutic effects of inhibitors such asmonoamine 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 withmonoamine 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.[12]
Inmammals, octopamine may mobilize the release offat fromadipocytes (fat cells), which has led to its promotion on theinternet 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 increaseblood pressure significantly when combined with otherstimulants, as in someweight loss supplements.[61]
TheWorld Anti-Doping Agency lists octopamine as a banned substance for in competition use, as a "specified stimulant"[62] on the 2019 Prohibited List.
The octopamine receptor is a target of insecticides, as its blockage leads to decreasedcyclic adenosine monophosphate (cAMP) levels. Essential oils can have such a neuro-insecticidal effect,[66] and this octopamine-receptor mechanism is naturally utilized by plants with active insecticidal phytochemicals.[67]
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.[70]
Octopamine acts as theinsect equivalent ofnorepinephrine and has been implicated in regulatingaggression ininvertebrates, with different effects on different species. Studies have shown that reducing the neurotransmitter octopamine and preventing coding oftyramine β-hydroxylase (anenzyme that convertstyramine to octopamine) decreases aggression inDrosophila without influencing other behaviors.[71]
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^Liu J, Wu R, Li JX (March 2020)."TAAR1 and Psychostimulant Addiction".Cell Mol Neurobiol.40 (2):229–238.doi:10.1007/s10571-020-00792-8.PMC7845786.PMID31974906.A recent study showed that TAAR1 mediates AMPH-induced activation of the downstreaming RhoA and cAMP signaling in HEK293 cells expressing DAT but not cells without DAT (Underhill et al. 2019). Interestingly, two different G proteins G13 and Gs regulated TAAR1 activation (Underhill et al. 2019). It was further shown that AMPH induced activation of both TAAR1-G13-RhoA and TAAR1-Gs-PKA signaling were dependent on DAT (Underhill et al. 2019). However, the TAAR1 agonist octopamine, which is not a substrate of DAT, did not activate RhoA signaling. Accordingly, it was suggested that these TAAR1/RhoA and TAAR1/PKA signaling pathways might be particular cascades that mediate the effects of amphetamines and could not generalize to other TAAR1 agonists (Underhill et al. 2019).
^Underhill SM, Hullihen PD, Chen J, Fenollar-Ferrer C, Rizzo MA, Ingram SL, et al. (April 2021)."Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains".Mol Psychiatry.26 (4):1208–1223.doi:10.1038/s41380-019-0469-2.PMC7038576.PMID31399635.Notably, the TAAR1 agonist octopamine (10 μM) did not activate RhoA in these cells (Fig. 1c). Octopamine is a potent activator of TAAR1 [4, 5] however, it is a poor substrate for DAT [23]. Because the DAT dependence of the effects of TAAR1 agonists on RhoA activation suggests that TAAR1 agonists act intracellularly to stimulate the receptor, we permeablized the HEK293 cells with streptolysin O to allow octopamine access to the cytoplasm [24]. In the presence of streptolysin O, octopamine produces an approximately twofold increase in activated Rho, whereas streptolysin O had no effect on its own, demonstrating that a TAAR1 agonist that is not a substrate for DAT can activate Rho-dependent signaling once it enters the cell. These studies also imply that entry through the DAT may not be prerequisite for activation of intracellular signaling by TAAR1; in fact, two recently-developed compounds from Roche (RO5166017 and RO5203648) show TAAR1 agonist activity in DAT KO mice and thus may gain access to the cell interior via other avenues [25, 26].
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Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages.See also:Receptor/signaling modulators
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