Adrenergic synapse

Within the varicosities, norepinephrine is stored in small membrane-enclosed vesicles (granules, 0.05-0.2 pm in diameter). In the Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

When stimulated electrically, the sympathetic nerve discharges the contents of part of its vesicles, including norepinephrine, into the extracellular space. Liberated norepinephrine reacts with adrenoceptors located postjunctionally on the membrane of effector cells or prejunctionally on the membrane of varicosities. Activation of pre-syn-aptic a2-receptors inhibits norepinephrine release. Through this negative feedback, release can be regulated. 

The effect of released norepinephrine wanes quickly, because -90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells). 

The liver is richly endowed with COMT and MAO it therefore contributes significantly to the degradation of circulating norepinephrine and epinephrine. The end product of the combined actions of MAO and COMT is vanillylmandelic acid. 

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Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Fig. 3. Schematic drawing of an adrenergic synapse. Nerve activity releases the endogenous neurotransmitter noradrenaline...

Because of the proliferation of adrenergic synapses in the CNS and the permeability of many of the following drugs into the brain tissue due to inherent lipophilicity or transport systems, several will be psychoactive as well as peripherally active. 

Figure 30-27 Some agonists and antagonists of adrenergic synapses (shown as cations in most cases).

Alpha-2 CNS inhibitory synapses Presynaptic terminal at peripheral adrenergic synapses Gastrointestinal tract Pancreatic islet cells Decreased sympathetic discharge from CNS Decreased norepinephrine release Decreased motility and secretion Decreased insulin secretion... 

Several agents are available that inhibit activity at adrenergic synapses by interfering with the release of norepinephrine. Rather than directly blocking the postsynaptic receptor, these drugs typically inhibit or deplete the presynaptic terminal of stored norepinephrine. These drugs are used primarily to decrease peripheral adrenergic influence and to treat problems such as hypertension and cardiac arrhythmias. 

The inhibition of adenylate cyclase. This is mediated by the inhibitory G protein (G ) a subunit. Triggers for this response include the adrenergic oc2-receptor, which is responsible for presynaptic feedback inhibition in adrenergic synapses, and the muscarinergic M2 receptor (Figure 8.2b). 

Neurotransmission at both cholinergic and adrenergic synapses can be influenced by a variety of naturally occurring and synthetic drugs (Table 38.2). For example, ACh secretion is drastically reduced in the presence of botulinum toxin which contains proteases that cleave proteins vital to the process of exocytosis. Nicotine, one of the active ingredients in tobacco can mimic the effects of ACh and increase (or decrease at high doses) autonomic ganglionic transmission as well as that at the... 

Lead has been shown to inhibit calcium competitively in a variety of biological systems, e.g. in the superior cervical ganglion of the cat (Kostial and Vouk, 1957) in presynaptic terminals in frog sympathetic ganglion (Kober and Cooper, 1977) in adrenergic synapses in the rabbit saphenous... 

The process of exocytosis also appears to apply to the release of NA from adrenergic nerves, since chromogranin-A and dopamine- -hydroxylase have been detected in the venous eflluent of perfused organs during nerve stimulation. A quantal release mechanism at adrenergic synapses is also supported by the finding that a spontaneous release of NA occurs from adrenergic nerves in various... 

In order to understand the mode of action of drugs on adrenergic synapses, it is essential to remember that the various biochemical systems which are present function and interact as a complex integrated whole. 

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