Catecholamines transmitters

As noted previously, indirect-acting sympathomimetics can have one of two different mechanisms (Figure 9-3). First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called amphetamine-like or "displacers." Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter, NET. 

In this area, too, neurobiological research has brought increasing knowledge. Cocaine and amphetamines act directly on synapses in the reward system to increase the amount of transmitter dopamine present. Several catecholamine transmitters are additionally involved in brain areas outside the reward system. This might explain the immediate effects, the euphoria produced, and the profile of the experiences. 

Adrenergic neurons (Figure 6-4) also transport a precursor molecule into the nerve ending, then synthesize the catecholamine transmitter, and finally store it in membrane-bound vesicles, but—as indicated in Figure 6-5—the synthesis of the catecholamine transmitters is more complex than that of acetylcholine. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, norepinephrine is further converted to epinephrine. Conversely, synthesis terminates with dopamine in the dopaminergic neurons of the central nervous system. Several important processes in these nerve terminals are potential sites of... 

A 1,2-dihydrobenzene structure, exemplified by the catecholamine transmitters noradrenaline and dopamine. 

Mechanism of action As with cocaine, the effects of amphetamine on the CNS and peripheral nervous system are indirect that is, they depend upon an elevation of the level of catecholamine transmitters in synaptic spaces. Amphetamine, however, achieves this effect by releasing intracellular stores of catecholamines (Figure 10.7). Since amphetamine also blocks monoamine oxidase (MAO), high levels of catecholamines are readily released into synaptic spaces. Despite different mechanisms of action, the behavioral effects of amphetamine are similar to those of cocaine. 

In addition to interfering with the reuptake of catecholamine transmitters, amphetamine will also release transmitter that is stored inside vesicles. This is different from reserpine, which only prevents uptake of more transmitter molecules into the vesicles but does not cause release of those already inside. The release itself can be demonstrated quite clearly with transmitter vesicles isolated form nerve tissue (Figure 10.17a) its mechanism, however, is still contentious. From several reports in the literature, 1 have distilled the modef depicted in Figure 10.17b. 

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

Although catecholamine transmitters have traditonally been considered feedback inhibitors of TH (Nagatsu et al., 1964 Spector et al., 1967 Weiner et al., 1972 Zigmond et al., 1989), these results suggest that, when combined with aFGF, catecholamines may instead act as feedback indue-... 

S5mthesized via tyramine (Fig. 30-26), apparently functions in place of noradrenaline. Note fhe precursor-product relationship between dopamine, noradrenaline, and adrenaline. The synthetic pathways to these neurotransmitters involve decarboxylation and hydroxylahon, types of reacfion imporfanf in formation of other transmitters as well. The most important process for ferminafing fhe acfion of released catecholamine transmitters is reuptake by the neurons. High-affinity uptake systems transport the catecholamine molecules back into the neurons and then into the synaptic vesicles. The uptake is specifically blocked by the drug reserpine (Fig. 25-12).7 The dopamine transporter is a major binding site for cocaine (see Fig. 30-28).7 7-7Si Catecholamine trans-miffers are catabolized by two enzymes. One is the... 

Adrenoceptor A receptor that binds—and is activated by—one of the catecholamine transmitters (norepinephrine, epinephrine, or dopamine) and reiated drugs... 

Mode of action Sympathomimetic agonists may directly activate their adrenoceptors, or they may act indirectly to increase the concentration of catecholamine transmitter in the synapse. Amphetamine derivatives and tyramine cause the release of stored catecholamines these sympathomimetics are therefore mainly indirect in their mode of action. Another form of indirect action is seen with cocaine and the tricyclic antidepressants these drugs inhibit reupmke of catecholamines by nerve terminals and thus increase the synaptic activity of released transmitter. 

Catecholamine reuptake pump Nerve terminal transporter responsibie for recycling catecholamine transmitters after release into the synapse... 

Other drugs modelled on catecholamine transmitters will be found in Section 12.4, e.g. phenylephrine (agonist) and methyldopa. 

Group 1 includes, in addition to serotonin and acetylcholine, histamine" and the catecholamine transmitters dopamine and norepinephrine. Each of these compounds is synthesised from a circulating precursor. The synthesis of each is catalysed by an enzyme (e.g. tryptophan hydroxylase for serotonin choline acetyltransferase for acetylcholine) that has a relatively low affinity for its substrate, and which thus normally operates at less-than-maximal efficiency (i.e. because it virtually never is fully saturated with the tryptophan or choline). Group 2 includes the various peptides that have been found in brain neurons which are thought by many scientists to function as neurotransmitters, largely because of their presence in neurons, and their ability to modify ionic fluxes when applied to brain neurons. These compounds almost certainly are synthesised not by enzymes but by polyribosomes (i.e. strands of messenger RNA attached to ribosomes). The concentrations of amino acids needed to allow polysome-directed peptide synthesis to occur at maximal rates in brain apparently are quite low hence, it doesn t seem likely that... 

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