Vesicles, adrenergic neuronal

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... 

Potential fates of recaptured norepinephrine Once norepinephrine reenters the cytoplasm of the adrenergic neuron it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential or persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid (VMA), metanephrine and normetanephrine. 

Indirect-acting agonists These agents, which include amphetamine and tyramine, are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (see Figure 6.8). As with neuronal stimulation, the norepinephrine then traverses the synapse and binds to the a or p receptors. 

As was noted on p. 68, some agonists, such as amphetamine and tyra-mine, do not act directly on the adrenoceptor. Instead, they exert their effects indirectly on the adrenergic neuron by causing the release of neurotransmitter from storage vesicles. Similarly, some agents act on the adrenergic neuron, to either interfere in neurotransmitter release or alter the uptake of the neurotransmitter into the adrenergic nerve. 

The antihypertensive mechanism of the rauwiloid alkaloids primarily involves depletion of catecholamines from stores by blocking their reuptake mechanism and thereby storage in neuronal vesicles. The effect is widespread both peripherally and centrally, and includes NE, DA, and 5-HT (serotonin). Depletion of the amines affects blood vessels, the heart, adrenal medulla, and possibly other tissues as well. Since it is the reuptake and not the release of NE that is inhibited in the postganglionic adrenergic neuron, the existing pool must be fully depleted before antihypertensive effects become apparent. The drug also binds to vesicular membranes for days, accounting for the irreversibility of the process. 

Methyldopa (a-methyl-3,4-dihydroxy-L-phenylalanine), an analog of 3,4-dihydroxyphenylalanine (DOPA), is metabolized by the L-aromatic amino acid decarboxylase in adrenergic neurons to a-methyldopamine, which then is converted to a-methylnorepinephrine. a-Methylnorepi-nephrine is stored in the secretory vesicles of adrenergic neurons, substituting for norepinephrine (NE) itself. Thus, when the adrenergic neuron discharges its neurotransmitter, a-methylnorepinephrine is released instead of norepinephrine. 

Fig. 1.5 Interactions at adrenergic neurones. A highly simplified composite diagram of an adrenergic neurone (molecules of noradrenaline (norepinephrine) indicated as ( ) contained in a single vesicle at the nerve-ending) to illustrate in outline some of the different sites where drugs can interact More details of these interactions are to be found in individual monographs.

Since catecholamines are stored in vesicles in chromaffin cells and adrenergic neurons, any model of the release mechanism must account for the passage of the... 

Neurotoxins such as mercaptopyrazide pyrimidine (MPP+) and 6-hydroxydopamine are also taken up by transporters, and this is required for their neurotoxic effects. Mice have been prepared with their transporter genes knocked out . Extensive studies with these mice confirm the important role of transporters (Table 12-1). Once an amine has been taken up across the neuronal membrane, it can be taken up by intracellular adrenergic storage vesicles as described above. 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

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. 

---