Noradrenaline does hang around in the cytoplasm unescorted, but generally speaking you need to keep your catecholamines in vesicles.
The VMAT-2 protein (vesicular amine transporter) concentrates the catecholamines in the vesicles. It is promiscuous: i.e. it has equal affinity for dopamine, adrenaline, noradrenaline, serotonin and so forth. VMAT-2 gets about 90% of the catecholamines into vesicles; the rest float about in the cytoplasm and get metabolized by mitochondrial MAO.
The low pH inside the vesicles causes the catecholamines to become trapped;
In the acidic environment they exist in their ionized water-soluble form, and thus cannot diffuse out
These vesicles act as storage for all kinds of monoamines. The VMAT-2 doesn’t care what it pumps.
If dopamine enters the vesicles, it gets converted to noradrenaline by dopamine beta-hydroxylase (dβH)
Catecholamine exocytosis is a process mediated by a bunch of proteins which have little clinical relevance outside of being the targets for the botulinum toxin and the tetanus toxin.
These proteins are SNAP-25, syntaxin and synaptobrevin.
Botulinum and tetanus toxins are more famous for this very same effect but at the neuromuscular junction.
Nobody quite knows precisely what mechanisms trigger the exocytosis of catecholamines at the nerve terminals, but it looks like it is something to do with calcium influx through voltage-gated N-type calcium channels. They open when the action potential reaches the synapse. The calcium influx then activates the vesicle fusion proteins, and exocytosis results.
Activation of presynaptic alpha-2 receptors inhibits the release of catecholamines . The specific alpha-2 receptor subtypes which act presynaptically are alpha-2A and alpha-2C
Activation of presynaptic beta-2 receptors enhances the release of catecholamines .
Activation of presynaptic A-1 adenosine receptors inhibits the release of catecholamines
This whole business with presynaptic receptors comes down to cyclic AMP.
If you increase cAMP (a β-2 effect), you enhance the release of catecholamines.
If you inhibit the production of cAMP (an α-2 or P1 adenosine receptor effect) the release of catecholamines will be decreased.
Removal of catecholamines from the synapse is effected by the NET and DAT proteins (NorEpinephrine Transporter and DopAmine Transporter). These make attractive drug targets.
α-Methyltyrosine blocks the conversion of tyrosine into L-DOPA, which is a rate-limiting step. This is one way of treating phaeochromocytoma.
α-Methyldopa blocks the conversion of L-DOPA into dopamine, and its active metabolite α-Methylnorepinephrine is an alpha-2 receptor agonist, which is functionally similar to clonidine.
Reserpine blocks VMAT-2, and can thus result in the depletion of catecholamines from all your nerve endings
Botulinum and tetanus toxins proteolyse the fusion proteins, synaptobrevin specifically, and thus prevent release of catecholamines and acetylcholine
Clonidine and dexmedetomidine act here to inhibit release of catecholamines.
Ditto α-Methylnorepinephrine as mentioned above.
Xanthines like caffeine act as adenosine antagonists; they inhibit the inhibition. The net result is an enhanced release of catecholamines.
Indirect sympathomimetics act here by displacing catecholamines out of the synapse and into the extracellular fluid.
Cocaine and the tricyclic antidepressants act at the NAT and DAT channels to decrease reuptake of noradrenaline, thus increasing its synaptic dwell-time.
Amphetamines also cause DAT and NET dysfunction, by causing internalization of the DAT protein, and by causing it to malfunction and actually leak dopamine back into the synapse