Noradrenaline transporter

Molecular target Gastrointestinal lipases Serotonin and noradrenaline transporter Cannabinoid-1 receptor... 

The most common treatment of ADHD is pharmacological. Psychostimulant diugs such as methylpheni-date and amphetamine or atomoxetin, an inhibitor of the noradrenaline transporter can be prescribed. These agents elicit the non-exocytotic release of... 

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

In common with other monoamines, the actions of released noradrenaline are terminated by its rapid reuptake from the synaptic cleft. This uptake process relies on membrane-bound noradrenaline transporters which are glycoproteins closely related... 

Pacholczyk, T, Blakely, RD and Amara, SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350 350-353. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose-response curve (Figure 7.3). 

Sharpe lA, Gehrmann J, Loughnan ML, Thomas L, Adams DA, Atkins A, Palant E, Craik DJ, Adams DJ, Alewood PF, Lewis RJ. (2001) Two new classes of conopeptides inhibit the alphal-adrenoceptor and noradrenaline transporter. Nat Neurosci 4 902-907. 

Which of the following does not have selectivity for the noradrenaline transporter over the serotonin transporter ... 

Rommelfanger KS, Weinshenker D, Miller GW (2004) Reduced MPTP toxicity in noradrenaline transporter knockout mice. J. Neurochem. 91 1116-1124. 

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... 

Various transporter proteins were assessed including P-glycoprotein (P-gp). The K-PLS classification models for P-gp substrates (Table 15.2, panel A) and K-PLS regression models for P-gp inhibitors (Table 15.2, panel B) were found to represent a slight improvement over PLS. The difference in favor of K-PLS is more pronounced for the noradrenaline transporter and serotonin transporter dissociation constant models (Table 15.2, panels C, D). 

Transporters, such as P-gp, play a key role in modulating the availability of drugs following absorption in the intestine and can also expel them from the brain [175-177], Other transporters of interest were the monoamine recognizing serotonin and noradrenaline transporters [123,124] and hOCTl... 

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