Transmitters false

MAO inhibitors will act peripherally and may act centrally, again depending on their pharmacokinetic properties. They have, like reserpine, been used for both antihypertensive and antipsychotic treatment but now been superseded by more selectively acting drugs. However, there recently has been renewed interest in the development of MAO B-selec-tive inhibitors, since that enzyme subtype acts preferentially on serotonin and in the central nervous system some of the side effects could thus be avoided or ameliorated. MAO B inhibitors have also been reported to increase the lifetime of dopamine and therefore to be beneficial in Parkinson s disease similarly, inhibitors of COMT have more recently been introduced as a supplement to therapy in this disease. 

Nice huh But most likely wrong. The same text does not fail to mention the so-called cheese reaction , which consists in a sudden rise of blood pressure in patients receiving MAO inhibitors. Cheese - as well as other t5q)es of fermented food, such as salami or summer sausage - is rich in decarboxylation products of amino acids (amines), which are in part responsible for the characteristic flavours. The one of interest here is indeed tyramine. Tyramine acts as an indirect S5mipathomimetic , much in the same way as amphetamine does. It can hardly be held responsible for lowering and increasing the blood pressure at the same 

Textbooks often have a deplorable tendency to explain the unexplained - thus preventing rather than stimulating independent thought. For an illustration, grab a really old textbook on whatever subject you like - if there is one thing UW has aplenty, it is outdated textbooks of any description. You may find lots of things explained that were completely unknown at the time. 

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Evidence for the false transmitter theory as the cause of encephalopathy is demonstrated by the fact that administration of flumazenil (a benzodiazepine antagonist) has resulted in functional improvement. Unfortunately, long-term benefit has not been shown, and since flumazenil can only be administered par-enterally, it is not an appropriate choice for long-term therapy. 

As indicated earlier, a-methyldopa treatment of hypertension sometimes results in the appearance of parkinsonian symptoms. This is presumed to be a consequence of DA depletion by replacement of DA with the relatively inactive false transmitter a-methyldopamine, as well as by inhibition of AADC (Ch. 12). 

When norepinephrine is substituted in the storage sites by amines of similar structure which are less agonistic, these agents are called "false transmitters." Until its central... 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Octopamine (4.41), which carries a p-hydroxyl group, is taken up even more readily into storage vesicles and is, in turn, released when the neuron fires. As an adrenergic agonist, octopamine is, however, only about one-tenth as active as NE therefore, it acts as a very weak neurotransmitter. Compounds such as this behave like neurotransmitters of low potency, and are called false transmitters. On the other hand, octopamine may be a true transmitter in some invertebrates, with receptors that cannot be occupied either by other catecholamines or by serotonin. 

Important intraspecies differences are found in the relative proportions of MAO-A or MAO-B in tissues [e.g., human brain has more MAO-B (about 70%) activity rat brain has more MAO-A]. After administration of an MAOI, intracellular levels of endogenous amines (e.g., NE) increase, but levels of amines not usually found in humans (tryptamine and phenylethylamine) also increase, followed by a compensatory decrease in amine synthesis because of feedback mechanisms. Levels of other amines or their metabolites (i.e., false transmitters) increase in storage vesicles and may displace true transmitters, while presynaptic neuronal firing rates decrease. After 3 to 6 weeks, brain serotonin may return to normal levels and NE levels may decrease. There is a compensatory decrease in the number of receptors, including b-adrenergic receptor-related functions (e.g., NE-stimulated adenyl cyclase). 

One pharmacological theory of the mechanism underlying postural hypotension is the false-transmitter theory. Tyramine may be metabolized to an inactive metabolite (octopamine) that partially fills the NE storage vesicles with a false (inactive) transmitter, but definitive proof is lacking. 

These drugs are best avoided in patients with cerebrovascular, cardiovascular and hepatic disorders. Some sympathomimetic effects may occur, mainly mild tremor and occasionally cardiac arrhythmias. Apparent anticholinergic effects may also occur but these are the result of sympathetic potentiation in tissues with dual cholinergic/adrenergic innervation, e.g. pupil. Sympatholytic effects can also occur, principally postural hypotension, because of synthesis of relatively inactive false transmitters, e.g. octopamine, in nerve terminals following inhibition of MAO and activation of alternative metabolic pathways. 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

The catecholamine-synthesizing enzymes are not only able to synthesize dopamine and norepinephrine from a physiologically occurring substrate such as levodopa, but also from exogenous substrates such as a-methyldopa, which is converted to a-methyldopamine and in turn to a-methylnorepinephrine. a-methyldopamine and a-methylnorepinephrine are called false transmitters and, in general (except for a-methylnorepinephrine), are weaker agonists, a-methyldopa is used in the management of hypertension. 

Another dmg closely similar to DOPA but used for different applications is a-methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the false transmitter a-methyl-dopamine. Like dopamine or norepinephrine, a-methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic a,-receptors, it does activate 0C2-receptors. It will therefore inhibit the further release of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accomplishes the same in a less roundabout manner). 

Like DOPA and methyldopa, 6-hydroxydopa (Figure 10.20a) finds its way into catecholaminergic nerve terminals it is decarboxylated inside the cell to 6-hydroxy-dopamine. The latter compound, however, does not act as a false transmitter. Instead, it acts as an inhibitor of the mitochondrial respiratory chain, apparently by binding to com-... 

Figure 10.19. False transmitters that are used for antihypertensive treatment, a a-Methyldopa passes the blood brain barrier and is decarboxylated to a-methyldopamine, which upon synaptic release stimulates presynaptic 02-receptors. b Guanethidine acts on catecholaminergic synapses in the peripheral autonomous nervous system.

A diagrammatic model of the probable actions of a neurotransmitter at the synapse is shown in figure 4. Drugs could alter neurotransmitter function by influencing one or more of these steps. Current theories as to the possible nature of the interaction of hallucinogenic drugs with serotonin and NE functions have tended to favor the concept that they function as false transmitters and can be bound into the receptor site in place of the endogenous neuro transmitters ... 

P450 to alpha-methyl-dopamine and further to alpha-methyl-noradrenaline, a CNS-active hypotensive agent that also may function as a false transmitter (Hoffman et al. 1979). Dougan and colleagues (1986) described the stereoselective neuronal accumulation of hydroxyamphetamine and hydroxynorephedrine in rat striatum and found them to have half-lives of 1.5 and 2.5 days, respectively, at this location. 

Examples of centrally acting antihypertensives are methyldopa and clonidine. Methyldopa becomes converted to methylnoradrenaline, which is a false transmitter with reduced effect on noradrenaline receptors in the brain. 

It is interesting that a hypotensive relapse occurs once the IV administration is discontinued. One explanation may be that the stored metaraminol being released from the NE-depleted neurons, since it is less effective as a pressor amine than NE, now acts as a false transmitter, actually having a hypotensive effect. Because of its a-CH3 it is not significantly affected by MAO (while the NE in the synaptic area is). Metaraminol will reaccumulate, be restored, and be re-released, thus prolonging the hypotensive effect. 

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