Bupropion transporters

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

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. 

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-... 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

Dopamine is removed from the synapse via two mechanisms. First, COMT degrades intrasynaptic DA. Second, the dopamine transporter (DAT) [see (4) in Fig. 2.9], a Na /CD-dependent neurotransmitter transporter, transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by drugs such as cocaine, amphetamine, bupropion, and nomifensine. 

Figure 2 List of precipitants evaluated with the substrates bupropion and efavirenz and which have shown more than 20% effect in in vivo inhibition. Display from the Metabolism and Transport Drug Interaction Database (http //www.druginteractioninfo...

Since dopamine is inactivated by norepinephrine reuptake in trontai cortex, A/hich iargeiy iacks dopamine transporters, bupropion can increase dopamine neurotransmission in this part ot the brain... 

Bupropion. The mechanism of action of bupropion (Wcllbutrin) is considered complex and reportedly involve-a block of DA rcuptakc via the dopamine transporter (DAT), but the overall antidepressant action is noradrenergic. A metabolite that contributes to the overall action and its fortiB-tion ean be easily rationali7.cd. 

The dopamine uptake system - or dopamine transporter system - is inhibited by the following clinically used agents amfonelic acid, bupropion, mazindot or experimental agents, nomifensine, indatraline, p-CFT, p-ClT-FP, GYKl 52895 and LR 5182. 

Some antidepressants, notably mazindol and bupropion (3), inhibit the dopamine transporter (DAT) as well as NET or SERT. The DAT is best known, however, as one of the principal sites of action of the psychostimulant drug cocaine. Mice that are genetically engineered to knock out the expression of the DAT gene are profoundly hyperactive and fail to show any further stimulation of activity in response to cocaine or (-i-)-amphetamine (109). Such animals, nevertheless, will continue to self-administer cocaine (110), suggesting that the rewarding properties of the... 

There are many pieces of evidence that indicate the rapid disappearance of DA following electrical stimulation observed in brain slices is due to uptake. The rate of disappearance of DA is far too quick in comparison to diffusion. Also, when the effect of diffusion through the thin Nation film is removed, no time lag between stimulation and DA uptake is observed in the disappearance as would be expected for diffusion [43]. Additionally, well-studied DA uptake inhibitors including bupropion, cocaine, and nomifensine [46,47], both in vivo and in brain slices, affect the rate of clearance. Lastly, a strain of mice was created that had the gene for DA transporter deleted [48]. In brain slices prepared from these uptake-deficient animals, stimulated DA remained in the extracellular fluid on a time scale consistent with that predicted for diffusion. 

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