Neurotransmitters false

False neurotransmitters resulting from increased levels of aromatic amino acids, high levels of y-aminobutyric acid, and endogenous benzodiazepines have also been implicated in HE. These substances bind to both the y-aminobutyric acid and benzodiazepine receptors and act as agonists at the active receptor sites.20... 

False neurotransmitters are amines which are similar enough in structure to normal amine neurotransmitters that they bind to receptors but are much less active or totally inactive (i.e. they are antagonists). One such false neurotransmitter is octopamine, which is formed from tyrosine by decarboxylation followed by side-chain hydroxylation. 

Compared to NE, the metabolism of the false neurotransmitter metaramind (MR), mediated by catechol-O-methyl transferase (COMT) and MAO, is reduced because of the absence of the catechol function and the presence of an a-methyl group, respectively (Fig. 24) [161],... 

The action of tyramine on nerve receptors is mainly indirect by release of norepinephrine and dopamine from neuronal storage sites (363, 384). Tyramine and its /3-oxidized counterpart octopamine have been referred to as false neurotransmitters because these compounds can be taken up, stored, and released from nerve endings in a way similar to those of the principal neurotransmitters norepinephrine and dopamine (385). Octopamine was first discovered in salivary glands of octopods (386). The compound is widely distributed in the animal kingdom and is present in high amounts in the nervous system of several species of invertebrates such as molluscs and arthropods, where it acts as a specific transmitter substance (387). Octopamine may also play a role in the regulation of adrenergic neurotransmission in mammals (387). Administration of octopamine to intact animals produces a transient rise in blood pressure (388). 

Zhang H, Gubernator NG, Staal RGW, Mosharov EV, Sulzer D, Sames D. Visualizing presynaptic activity of individual striatal dopamine terminals with fluorescent false neurotransmitters. Program No. 354.4. 2007 Neuroscience Meeting Planner. Society for Neuroscience, San Diego, CA. 

False neurotransmitters. A number of substances, in some cases structurally related to the biogenic amines, are considered to act as false neurotransmitters and GC-MS methods have been applied to their detection. Thus, p-hydroxynorephedrine, a metabolite of (-l-)-amphetamine, can apparently replace noradrenaline and be taken up and released by a similar mechanism to that involved for the catecholamine. A quantitative SIM assay for this metabolite (as the pentafluoropropionyl derivative) has been used in studies of its formation and localisation in brain regions of the rat [473]. Similar methods have been applied to the detection in neural tissue of the N-dealkylated metabolites of methamphetamine, which depletes brain noradrenaline and fenfluramine which depletes serotonin [474]. 

Neuro transmitter hypothesis Apart from a disorder of the postsynaptic receptors, discussion centres on (1.) formation of false neurotransmitters such as octopamine and phenylethanolamine due to the accumulation of phenylalanine and tyrosine, (2.) decrease in excitatory neurotransmitters such as dopamine and noradrenaline, and (3.) increase in inhibitory neurotransmitters, such as GABA and serotonin. 

The application of branched-chain amino acids (BCAA) was based on the therapeutic target of compensating for the surplus of aromatic amino acids in order to suppress the synthesis of false neurotransmitters. Nevertheless, up to now, (7.) no correlation has been found between the amino acid imbalance in the plasma and the degree of severity of HE, (2.) no temporal correlation has been established between the normalization of the amino acid imbalance and the improvement of HE, and (3.) no influence has been detected on normal neurotransmitters in the CSF. These three counterarguments are, however, the subject of controversy and critical discussion. 

Fischer, J.E., Baldessarini, R.J. False neurotransmitters and hepatic failure. Lancet 1971/11 75-80... 

The numerous biochemical substances that may be considered with regard to hepatic encephalopathy or ascites have been outlined in detail, (s. tabs. 15.2 16.5) Similarly, an extensive synopsis of pathogenetically effective biochemical factors can be drawn up for HRS as well. All of them ultimately interfere — directly or indirectly - with the renal retention or excretion of sodium and/ or the balance between vasodilation and vasoconstriction. RAAS is markedly activated. (5, 28, 33, 41, 62, 64, 65) (s. tab. 17.1) Vasodilative factors under discussion include bilirubin, bile acids, nitrogen monoxide (NO), false neurotransmitters, calcitonin peptide (25) as well as platelet-activating factor (RAF). In more recent studies, considerably higher plasma values of the vasoconstrictor leukotrienes (C4 and D4) (41) and endothehn 1 and 3 (42) were detected. 

Ibotenic acid is structurally similar to glutamic acid, whereas muscimol closely resembles gamma-aminobutyric acid (GABA). Muscimol has an affinity for GABA receptors in the central nervous system, functioning as a false neurotransmitter, and appears to mimic the effects of GABA. 

The effect of 2,4,5-T was investigated in in vitro studies with sublethal concentrations of 2,4,5-T, which showed an inhibitory effect on calcium-dependent ATPase. In vivo exposure to various sub-lethal concentrations of 2,4,5-T during 96 h caused a significant inhibition of microsomal calcium-dependent ATPase. 2,4,5-T inhibits renal anion transport. Exposure of cells to 2,4,5-T resulted in a dose-de-pendent inhibition of DNA synthesis. Also, 2,4,5-T was shown to combine with choline to form 2,4,5-T-acetylcholine, a false neurotransmitter that inhibited muscle contraction. Since the false neurotransmitter could be formed at muscarinic as well as nicotinic synaptic sites, this interference with cholingeric neurotransmission may at least partially explain myotonia, ventricular fibrillation, and fetal growth retardation reported after 2,4,5-T exposure. Einally,... 

The "False Neurotransmitter" concept as a basis for explaining the mechanism of the hypotensive action of MAO-I s is presented in greater detail by Gohen et al.61. The delayed action of the MAO-I s with respect to their clinical antidepressant and hypotensive activities is presumably due to an indirect effect dependent on the gradual accumulation of monoamines at the adrenergic nerve fibres. According to the... 

GABA)-benzodiazepine receptors by flumazenil and (c) inhibition of false neurotransmitters by optimizing amino acid balance. ... 

BCAAs) is superior to standard protein solutions that are higher in aromatic amino acids (AAAs)J Metabolism of AAAs into false neurotransmitters that penetrate the blood-brain barrier (which itself may be perturbed in patients with HE) has been implicated as a cause of HE. A number of clinical trials have evaluated the use of BCAAs in the treatment of HE, with conflicting results. Reviews of these trials have also arrived at different conclusions. BCAAs may have a role in the malnourished patient with cirrhosis who is intolerant of protein supplementation, but the current data do not justify routine use of BCAAs for the treatment of HE. Impairment of dopaminergic transmission has also been proposed to cause HE, but trials with bromocriptine and levodopa failed to provide any benefit and are not recommended. ... 

The major controversy in nutritional support of the patient with liver failure has centered around the use of protein products. Modified amino acid solutions for PN (HepatAmine, others) are marketed for patients with liver failure and hepatic encephalopathy. They are enriched with BCAAs and have reduced amounts of AAAs and methionine. The products are formulated on the basis of the false neurotransmitter hypothesis, which concludes that hepatic encephalopathy may be due to increased AAA concentrations in the central nervous system. 

Figure 10. Metabolites of a-methyl DOPA which could act as false neurotransmitters. a-Methyl DOPA acts in the form of its decarboxylated...

Possible mechanisms of actions are (a) competitive displacement of NE from binding sites (b) false neurotransmitter with respect to release on sympathetic stimulation and adrenergic receptor interaction (c) false neurotransmitters with respect to causing negative feedback on CA biosynthesis. In its clinical action it is widely used as an antihypertensive. 

The model scheme (Figure 18) developed by Iversen illustrates some of the theories which have been advanced to explain the action of the tricyclic antidepressant and antipsychotic drugs, as well as that of reser-pine, amphetamine, and the false neurotransmitters. 

False neurotransmitters could act at various neuronal levels by inhibiting the uptake of NE, by interfering with sufficient release of the true transmitter, or by operating as stimulators of negative feedback of dopamine and NE biosynthesis. 

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