Norepinephrine noradrenaline transporter

Atomoxetine is the most recent neurotransmitter reuptake inhibitor to reach the market (Fig. 2.3). It is a selective inhibitor of norepinephrine (noradrenaline) transport, and during the 1980s was - as tomoxetine - evaluated clinically for the... 

Figure 2.10 Amphetamine 30, methamphetamine 31, and methylenedioxymethamphetamine 32 (MDMA, ecstasy, XTC) are lipophilic compounds with good oral bioavailability they easily cross the blood-brain barrier to exert central nervous system effects. Dopamine 33, norepinephrine (noradrenalin) 34, and epinephrine (adrenaline) 35 are polar phenethylamines they have poor oral efficacy and do not pass the blood-brain barrier, producing only peripheral effects after intravenous application. Ephedrine 36 has intermediate lipophilicity besides its peripheral effects it also acts as a central stimulant. Although L-dopa 37 is even more polar than dopamine 33, it is orally active and crosses the blood-brain barrier by active transport mediated by the amino acid transporter.

Some less obvious phenomena of catecholamine transport and biosynthesis further illustrate the complexities of deciphering how efferents from midbrain dopamine neurons contribute to sleep-wake regulation. The plasma membrane norepinephrine transporter (NET), which is responsible for the uptake of extracellular noradrenaline, can also readily transport dopamine, and does so in vivo. This... 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-hydroxytryptamine (5-HT)], norepinephrine [NE noradrenaline (NA)], or both. They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a neurotransmitter receptor. Hence, the antidepressants can be classified on the basis of their putative mechanisms of action (Table 8.2 and Figs. 8.1-8.4). Agents that block neurotransmitter reuptake can be further divided into those that are non-selective (e.g., tricyclic antidepressants with mixed action), serotonin-selective reuptake... 

Moderate affinity for the specific receptor/transporter NARI Selective noradrenaline (norepinephrine) reuptake inhibitor... 

This mechanism acts in the inactivation of neiu-otransmitters as serotonin = 5-hydroxytryptamine (5-HT), noradrenaline = norepinephrine (NE) and dopamine (DA). The re-uptake is effected by selective transporters for each neurotransmitter. 

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