Norepinephrine reuptake transporter

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

Atomoxetine (Straterra , originally tomoxetine or tomoxetin, 3) was first described and synthesized by chemists at Eli Lilly in the late 1970s and was one of the few compounds that was known to display meaningful selectivity for the norepinephrine reuptake transporter (NET) versus the serotonin reuptake transporter (SERT) and the dopamine reuptake transporter (DAT) (Barnett, 1986 Molloy and Schmiegel, 1997). Atomoxetine was one of several structurally related and commercially successful monoamine reuptake inhibitors that were developed by Lilly for the treatment of various psychiatric disorders (Eig. 17.4). Fluoxetine (43) and duloxetine (44) have both gained approval in the United States as Prozac and Cymbalta , respectively, and nisoxetine (45) is widely used as a tool in biology. 

Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, particularly during sympathetic stimulation, and this... 

NET, norepinephrine reuptake transporter SERT, serotonin reuptake transporter. ... 

CNS, central nervous system GI, gastrointestinal SERT, serotonin reuptake transporter NET norepinephrine reuptake transporter CB, cannabinoid tid, three times daily qd, daily. 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

Pharmacology Lithium alters sodium transport in nerve and muscle cells, and effects a shift toward intraneuronal catecholamine metabolism. The specific mechanism in mania is unknown, but it affects neurotransmitters associated with affective disorders. Its antimanic effects may be the result of increases in norepinephrine reuptake and increased serotonin receptor sensitivity. Pharmacokinetics ... 

Pharmacology Atomoxetine is a selective norepinephrine reuptake inhibitor. The precise mechanism by which it produces its therapeutic effects in ADHD is unknown, but it is thought to be related to selective inhibition of the presynaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. Pharmacokinetics ... 

Atomoxetine is a selective inhibitor of norepinephrine presynaptic reuptake transporters that has been shown to increase extracellular norepinephrine and dopamine concentrations in the prefrontal cortex in rats (Bymaster et al. 2002), which may account for its clinical efficacy in the treatment of ADHD symptomatology. However, atomoxetine does not appear to affect dopamine levels in the striatum or nucleus accumbens and consequently is not thought to carry the abuse potential associated with stimulant medications. 

MDR1, multidrug resistance protein-1 MRP1, multidrug resistance-associated protein 1 NET, norepinephrine transporter SERT, serotonin reuptake transporter VMAT, vesicular monoamine transporter. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

Methylphenidate s mode of action is not completely known, but it is believed that ADHD symptoms are related to the dopaminergic areas of the brain. Animal studies indicate that methylphenidate affects several neurotransmitters to counteract ADHD behavior. Methylphenidate binds to dopamine transporters in the presynaptic neuron, blocking the reuptake of dopamine and increasing extracellular dopamine. Methylphenidate also influences norepinephrine reuptake and influences serotonin to a minor degree. 

FIGURE 12-4. The enantiomer of -amphetamine is /-amphetamine, which has no preference between the norepinephrine and the dopamine transporters. Thus, it will target both the norepinephrine reuptake site (shown here), as well as the dopamine reuptake site (shown in Fig. 12-2). -Amphetamine is selective for the dopamine transporter. 

FIGURE 12—5. Here, /-amphetamine is releasing norepinephrine from presynaptic noradrenergic neurons. It also does this from dopamine neurons, just as shown for (/-amphetamine in Figure 12—3. When /-amphetamine binds to ther-presynaptic norepinephrine transporter on the norepinephrine presynaptic nerve terminal, it not only blocks norepinephrine reuptake but actually causes norepinephrine release. Thus, /-amphetamine releases both norepinephrine and dopamine, whereas (/-amphetamine is selective for dopamine. Since norepinephrine and dopamine can have different if related cognitive functions in different patients, then d- and /-amphetamine can have different cognitive effects as well. 

Venlafaxine is a potent inhibitor of serotonin reuptake and a weaker inhibitor of norepinephrine transport such that at lower therapeutic doses it behaves like an SSRI. At high doses (more than 225 mg/d) it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine reuptake inhibition. Doses in the range of 300 mg/d or greater may confer broader therapeutic effects than SSRIs, but a careful titration up to these doses is needed to control adverse effects. 

NE molecules released into the synaptic space are reabsorbed back into the presynaptic neuron by the membrane NE transporter (NET). This process requires ATP. The NET is a target for numerous drugs. Several tricyclic antidepressants (TCA), such as imipramine, non-specifically inhibit both NET and 5-HT (5-HTT) transporters (Corrodi and Fuxe 1968). Other TCAs, called norepinephrine reuptake inhibitors (NRIs), such as desipramine, specifically inhibit the NET (Curet et al., 1992 Lacroix et al., 1991). There are also non-tricyclic selective inhibitors of the NET, called selective norepinephrine reuptake inhibitors (SNeRIs), and dual inhibitors of the NET and 5-HTT (SNRIs). The examples for SneRIs and SNRIs are reboxetine and venlafaxine, respectively (Beique et al., 1998a Beique et al., 1998b Beique et al., 1999 Dawson et al., 1999 Szabo and Blier 2001c). 

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... 

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... 

Again, there are various dmgs with different ranges and specificities. Cocaine has a particularly broad spectrum, affecting the reuptake of norepinephrine, dopamine, and serotonin alike. The effect of cocaine can be quantitatively studied in mice by observing their excitement in response to being placed into a new environment, which is measured simply as the distance travelled within their new home over time. In experiments with transgenic mice, the reuptake transporters for both dopamine and serotonin had to be deleted in order to abolish the increase in excitement induced by cocaine. 

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission... 

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, amitriptyline can increase dopamine neurotransmission in this part of the brain... 

A more potent inhibitor of norepinephrine reuptake pump than serotonin reuptake pump (serotonin transporter)... 

Biocks norepinephrine reuptake pumps, aiso known as norepinephrine transporters... 

---