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The octopamine and tyramine, as the invertebrate counterparts of the vertebrate adrenergic transmitters, control and modulate many physiological and behavioral processes. Both molecules mediate their effects by binding to specific receptors belonging to the superfamily of G-protein-coupled receptors. So far, four families of octopamine and tyramine receptors have been reported. Here, we described the functional characterization of one putative octopamine/tyramine receptor gene from the rice stem borer, Chilo suppressalis. By a mechanism of alternative splicing, this receptor gene (CsOA3) encodes two molecularly distinct transcripts, CsOA3S and CsOA3L. CsOA3L differs from CsOA3S on account of the presence of an additional 30 amino acids within the third intracellular loop. When heterologously expressed, both receptors cause increases of intracellular Ca2+ concentration. The short form, CsOA3S, was activated by both octopamine and tyramine, resulting in decreased intracellular cAMP levels ([cAMP]i) in a dose-dependent manner, whereas dopamine and serotonin are not effective. However, CsOA3L did not show any impact on [cAMP]i. Studies with series of agonists and antagonists confirmed that CsOA3 has a different pharmacological profile from that of other octopamine receptor families. The CsOA3 is, to our knowledge, a novel family of insect octopamine receptors. Octopamine, the invertebrate counterpart of noradrenaline, modulates many physiological processes. Four families of octopamine/tyramine receptors have been reported. We found that a novel family of octopamine receptors, which encodes two transcripts by alternative splicing, couple with different second messenger pathways. It implicated that one octopamine receptor gene could play different functional roles by alternative splicing.

Brain norepinephrine and dopamine regulate a variety of critical behaviors such as stress, learning, memory, and drug addiction. In this study, we demonstrate differences in the regulation of in vivo neurotransmission for dopamine in the anterior nucleus accumbens (NAc) and norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat. Release of the two catecholamines was measured simultaneously using fast-scan cyclic voltammetry at two different carbon-fiber microelectrodes, each implanted in the brain region of interest. Simultaneous dopamine and norepinephrine release was evoked by electrical stimulation of a region where the ventral noradrenergic bundle, the pathway of noradrenergic neurons, courses through the ventral tegmental area/substantia nigra, the origin of dopaminergic cell bodies. The release and uptake of norepinephrine in the vBNST were both significantly slower than for dopamine in the NAc. Pharmacological manipulations in the same animal demonstrated that the two catecholamines are differently regulated. The combination of a dopamine autoreceptor antagonist and amphetamine significantly increased basal extracellular dopamine whereas a norepinephrine autoreceptor antagonist and amphetamine did not change basal norepinephrine concentration. α-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, decreased electrically evoked dopamine release faster than norepinephrine. The dual-microelectrode fast-scan cyclic voltammetry technique along with anatomical and pharmacological evidence confirms that dopamine in the NAc and norepinephrine in the vBNST can be monitored selectively and simultaneously in the same animal. The high temporal and spatial resolution of the technique enabled us to examine differences in the dynamics of extracellular norepinephrine and dopamine concurrently in two different limbic structures.

The cytochrome P450-mediated synthesis of dopamine from tyramine has been shown in vitro. The aim of the present study was to demonstrate the ability of rat cytochrome P450 (CYP) 2D to synthesize dopamine from tyramine in the brain in vivo. We employed two experimental models using reserpinized rats with a blockade of the classical pathway of dopamine synthesis from tyrosine. Model A estimated dopamine production from endogenous tyramine in brain structures in vivo (ex vivo measurement of a tissue dopamine level), while Model B measured extracellular dopamine produced from exogenous tyramine (an in vivo microdialysis). In Model A, quinine (a CYP2D inhibitor) given intraperitoneally caused a significant decrease in dopamine level in the striatum and nucleus accumbens and tended to fall in the substantia nigra and frontal cortex. In Model B, an increase in extracellular dopamine level was observed after tyramine given intrastructurally (the striatum). After joint administration of tyramine and quinine, the amount of the dopamine formed was significantly lower compared to the group receiving tyramine only. The results of the two complementary experimental models indicate that the hydroxylation of tyramine to dopamine may take place in rat brain in vivo, and that CYP2D catalyzes this reaction.

It is now recognized that trace amine associated-receptor 1 (TAAR1) plays a functional role in the regulation of brain monoamines and the mediation of action of amphetamine-like psychostimulants. Accordingly, research on TAAR1 opens the door to a new avenue of approach for medications development to treat drug addiction as well as the spectrum of neuropsychiatric disorders hallmarked by aberrant regulation of brain monoamines. This overview focuses on recent studies which reveal a role for TAAR1 in the functional regulation of monoamine transporters and the neuronal regulatory mechanisms that modulate dopaminergic activity.

In invertebrates, the biogenic-amine octopamine is an important physiological regulator. It controls and modulates neuronal development, circadian rhythm, locomotion, ‘fight or flight’ responses, as well as learning and memory. Octopamine mediates its effects by activation of different GTP-binding protein (G protein)-coupled receptor types, which induce either cAMP production or Ca2+ release. Here we describe the functional characterization of two genes from Drosophila melanogaster that encode three octopamine receptors. The first gene (Dmoa1) codes for two polypeptides that are generated by alternative splicing. When heterologously expressed, both receptors cause oscillatory increases of the intracellular Ca2+ concentration in response to applying nanomolar concentrations of octopamine. The second gene (Dmoa2) codes for a receptor that specifically activates adenylate cyclase and causes a rise of intracellular cAMP with an EC50 of ∼3 × 10−8 m octopamine. Tyramine, the precursor of octopamine biosynthesis, activates all three receptors at ≥ 100-fold higher concentrations, whereas dopamine and serotonin are non-effective. Developmental expression of Dmoa genes was assessed by RT–PCR. Overlapping but not identical expression patterns were observed for the individual transcripts. The genes characterized in this report encode unique receptors that display signature properties of native octopamine receptors.

In invertebrates, the phenolamines, tyramine and octopamine, mediate many functional roles usually associated with the catecholamines, noradrenaline and adrenaline, in vertebrates. The α- and β-adrenergic classes of insect octopamine receptor are better activated by octopamine than tyramine. Similarly, the Tyramine 1 subgroup of receptors (or Octopamine/Tyramine receptors) are better activated by tyramine than octopamine. However, recently, a new Tyramine 2 subgroup of receptors was identified, which appears to be activated highly preferentially by tyramine. We examined immunocytochemically the ability of CG7431, the founding member of this subgroup from Drosophila melanogaster, to be internalized in transfected Chinese hamster ovary (CHO) cells by different agonists. It was only internalized after activation by tyramine. Conversely, the structurally related receptor, CG16766, was internalized by a number of biogenic amines, including octopamine, dopamine, noradrenaline, adrenaline, which also were able to elevate cyclic AMP levels. Studies with synthetic agonists and antagonists confirm that CG16766 has a different pharmacological profile to that of CG7431. Species orthologues of CG16766 were only found in Drosophila species, whereas orthologues of CG7431 could be identified in the genomes of a number of insect species. We propose that CG16766 represents a new group of tyramine receptors, which we have designated the Tyramine 3 receptors.

We investigated, by microdialysis in various brain areas, the possibility that dopamine could be captured by the norepinephrine transporter when the dopamine transporter is pharmacologically blocked. Administration of reboxetine, a selective blocker of the norepinephrine transporter, 20 min after the administration of GBR 12909, a selective blocker of the dopamine transporter, produced an increase of dopamine output in the nucleus accumbes shell (+408% above basal) greater than that obtained by GBR 12909 alone (+308% above basal). On the contrary, reboxetine did not increase further the dopamine output produced by GBR 12909 in the nucleus accumbens core or in the dorsal caudate, areas lacking a consistent noradrenergic innervations. A cumulative effect of dopamine and norepinephrine transporter blockade on the output of dopamine in dialysates was also observed in the bed nucleus of stria terminalis and in the prefrontal cortex. This study shows that dopamine extracellular concentration can be elevated by norepinephrine transporter blockade, even in areas where the dopamine transporter is predominant, when the latter is pharmacologically blocked. This phenomenon may have relevance in psychostimulant dependence as well as in antidepressant pharmacology.

The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.

There is growing evidence of an interaction between dopamine and norepinephrine. To test the hypothesis that norepinephrine terminals are involved in the uptake and removal of dopamine from the extracellular space, the norepinephrine uptake blocker desmethylimipramine (DMI) was infused locally while the extracellular concentrations of dopamine were simultaneously monitored. DMI increased the extracellular concentrations of dopamine in the medial prefrontal cortex and nucleus accumbens shell but had no effect in the striatum. The combined systemic administration of haloperidol and the local infusion of DMI produced an augmented increase in extracellular dopamine in the cortex compared with the increase produced by either drug alone. This synergistic increase in dopamine overflow is likely due to the combination of impulse-mediated dopamine release produced by haloperidol and blockade of the norepinephrine transporter. No such synergistic effects were observed in the nucleus accumbens and striatum. Local perfusion of the alpha2-antagonist idazoxan also increased the extracellular concentrations of dopamine in the cortex. Although the stimulation of extracellular dopamine by idazoxan and DMI could be due to the increased extracellular concentrations of norepinephrine produced by these drugs, an increase in dopamine also was observed in lesioned rats that were depleted of norepinephrine and challenged with haloperidol. This contrasted with the lack of an effect of haloperidol on cortical dopamine in unlesioned controls. These results suggest that norepinephrine terminals regulate extracellular dopamine concentrations in the medial prefrontal cortex and to a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norepinephrine transporter.

— Axoplasmic transport of dopamine in the nigro-neostriatal system has previously been shown by the specific accumulation of labelled dopamine in the striatum following injections of labelled DOPA or dopamine into the substantia nigra. To test the specificity, 17 different labelled materials (pipecolic acid, inulin, taurine, GABA, glycine, histidine, histamine, serotonin, 5-HTP, D-amphetamine, 3-methoxytyramine, dopamine, tyramine, norepinephrine, octopamine and high and low specificity activity DOPA) were injected into the substantia nigra and the distribution of radioactivity in the brain studied after 6 and 24 h. Only the catecholamines and octopamine gave evidence of specific accumulation in the ipsilateral striatum although some of the other compounds caused diffuse labelling of the striatum along with other brain areas.

— Octopamine is a normally occurring amine in several species of animals. Particularly high concentrations are found in the crustacean central nerve cord. In the rat it is specifically localized to sympathetic nerve endings, has a subcellular distribution similar to that of norepinephrine, and is asymmetrically distributed in the CNS. It has a turnover rate in heart about six times that of norepinephrine. The physiological role of octopamine has not been established but it appears likely that it is a cotransmitter together with norepinephrine in the peripheral sympathetic nervous system.