False Transmitters

Sourkes reported that a-methylDOPA inhibited DOPA decarboxylase in 1954. Its antihypertensive actions were initially ascribed to this effect. However, decarboxylase inhibition did not explain its antihypertensive action. Drug administration led to a-methyldopamine storage in the brain and sympathetic nerves. Carlsson and Lindqvist contrasted reserpine-induced monoamine depletion with that caused by the DOPA analogs, a-methyldopa and a-methyl-m-tyrosine [39]. Carlsson and others proposed that a-methyldopa's antihypertensive action was due to displacement of the natural transmitter [40]. Stimulation of cardiac sympathetic nerves liberated a-methylnoradrenaline from the heart of a-methyldopa treated rabbits [41]. Haefely et al. showed that the ratio of a-methylnoradrenaline to noradrenaline released by splenic nerve stimulation correlated with that found in the spleen [42]. However the relationship between storage of the false transmitter a-methyl NA and the effects of a-methyl dopa on sympathetic nerve function was complex. Figure 5 illustrates the complexity of false transmitter actions. The response to intravenous noradrenaline was little changed by pretreatment with either of two false transmitters, a-methyl dopa or a-methyl-meta-tyrosine, but tyramine injections had different effects. Haefely and colleagues also found that contractions of the nictitating membrane evoked by sympathetic stimulation were not consistently decreased in spite of marked displacement of NA by the two false transmitters (their figure 2, not shown here).

Reserpine eliminates all stored amines, while the decarboxylated DOPA analogs displace the natural transmitter from storage vesicles. They are released from the storage sites but are less potent than the natural transmitter. Decarboxylation and subsequent P-hydroxylation of a-methyl-meta-tyrosine produces metaraminol. It is much less potent than noradrenaline, so that replacement of the physiological transmitter with metaraminol should produce a greater sympathetic deficit than replacement with a-methylnoradrenaline. Udenfriend and Zaltzman-Nirenberg showed that a-methyl-meta-tyrosine (a-MMT) must be decarboxylated in order to release NA from the guinea pig heart (Figure 6). Metaraminol and other metabolic products of a-MMT were potent NA releasers [43]. Crout and coworkers showed that sympathetic nerve stimulation released metaraminol from the perfused cat heart after injections of metaraminol [44].

Decarboxylation is necessary for NA release by AMM

0 50 100 150 200 250 300 350 400

dose of decarboxylase inhibi'

Figure 6. This figure 6 uses data from reference 43. Guinea pigs received one injection of a, P-methylene a-MMT and variable doses of the decarboxylase inhibitor a-methyl dopa hydrazine and were killed 16 hrs later. As decarboxylation is progressively inhibited, a-MMT released progressively less NA from the heart.

Monoamine oxidase inhibition reduces blood pressure and causes octopamine accumulation in sympathetic nerves [45]. Blood and tissue content of tyramine and many other amines increase. Octopamine is synthesized from tyramine and acts as a false transmitter [46]. However, octopamine is a primary transmitter in other circumstances, with its own receptors. Octopamine was identified as a lobster neurotransmitter in the early 1970s [47] and was soon found in many more invertebrates. Peter Evans suggested in 1978 that it functioned in invertebrates much as noradrenaline does in vertebrates, as the primary sympathetic nervous system messenger [48]. Octopamine receptors were abundant, and their drug responses generally resembled those of mammalian a- adrenergic receptors.

Octopamine appears to be a stress hormone in many insects [49]. Its uptake, receptors and second messengers are analogous to those for catecholamines; it regulates learning and complex behavior in many invertebrates [49,50]. Small amounts of tyramine and octopamine are found in all mammals. This is easily understood from the reactions shown below (Figure 7). Larger amounts of octopamine accumulate in hepatic encephalopathy [51]; certain fermented foods are rich in tyramine and octopamine [52].

The amino acids

, i i - abundant decarboxylase activity phenylalanine .

tyrosine W

dihydroxyphenylanine (DOPA)

Octopamine synthesis Mammals tyramine Insects tvramine

The amines phenylethylamine tyramine dopamine

NH, tyniminr 11 hydm\ylnsr octopamine octopamine

Figure 7. Octopamine is produced by hydroxylation of tyramine. Tyramine hydroxylation by dopamine P hydroxylase is a minor pathway in mammals. Tyramine synthesis by a separate but related enzyme, tyramine P hydroxylase, is a major pathway in insects.

The classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). Borowsky and coworkers discovered a new GCPR family responding to tyramine and P-phenylethyl-amine but not to classical biogenic amines in 2001 [53]. Several closely related genes were identified and designated as trace amine associated receptors [TAARs]. Many of these TAAR subtypes respond poorly to tyramine, P-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands [54]. However, TAAR-1 modulates dopaminergic and motor function [55] and some trace amines probably have direct vascular effects [56]. These receptors may be useful therapeutic targets in human disease including psychiatric diseases [57].

Limited specificity of the transport, synthesis, storage and release machinery meant that many false transmitters could be created, such as octopamine from tyramine. DOPA replacement therapy for Parkinson's disease produces dopamine accumulation in nondopaminergic nerve endings; part of its effect is a false transmitter effect. The NA precursor L-threo-3, 4-dihydroxyphenylserine (DOPS) and the serotonin precursor 5-hydroxytryptophan (5-HTP) have similar effects, but they are used much less frequently than

DOPA is. The clinical use of a-methyl Dopa, like reserpine, is mostly of historical interest because better antihypertensive drugs are now available. Metaraminol and other sympathomimetic amines are used less freely for hypotension and shock than they were in 1970 because many other treatments are now available [58]. Metaraminol's false transmitter action means that its initial pressor effect, due to NA release, may be followed by hypotension if infusion continues, as metaraminol displaces stored NA [59].

Owman and others reported in the 1960s that pineal adrenergic nerves appeared to contain two different signaling amine molecules: 5-HT and octopamine [60,61]. Soon thereafter, Zweig and Axelrod reported a reciprocal relationship between pineal content of NA and 5-HT. Depletion of one amine produced an increase in the other [62]. This was a stable relationship unlike false transmitters related to drug therapy. The pineal situation became even more complex as octopamine appeared to follow the same pattern, increasing to fill storage space when 5-HT was depleted [63]. Pineal octopamine content increased when rats received tyramine and a MAO inhibitor; it fell when the rats received reserpine [64]. This illustrates multiple stable transmitters and competition between related amines for storage space.

The arylalkylguanidine meta-iodobenzylguanidine (MIBG) is structurally similar to noradrenaline [65]. It is a false transmitter that is concentrated within secretory granules of catecholamine-producing cells [66,67]. Iodinated MIBG is used for localization of neural crest tumors such as neuroblastoma and pheochromocytoma. The first use of 131I-MIBG to localize a pheochromocytoma was in 1981 [68]. MIBG does not cross the blood-brain barrier. A recent study used a fluorescent false transmitter to monitor dopamine release from living mouse striatal slices [69]. This study showed that the fraction of synaptic vesicles releasing transmitter with each stimulus was a function of stimulus frequency. False transmitters remain a useful research tool; they have a small place in clinical medicine.

Table 1. Synopsis of false transmitters

Thesis

A neuron releases the same transmitter at all branches; transmitter identity never changes.

Antithesis

Endogenous or exogenous amines may displace natural amine transmitters and be released by nerve stimulation

Synthesis

Transmitter uptake, storage and synthesis are only partially specific. Drug treatment, disease and unusual diets may produce false transmitters, with or without physiological consequences

Reconsideration

False transmitters have multiple effects. Some classical false transmitters, such as octopamine, act at trace amine-activated receptors in addition to their false transmitter actions

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Responses

  • Gloria
    How false transmitters are used in therapy?
    9 months ago

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