Dopamine-selective reuptake antidepressants

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). 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

MAOI, monoamine oxidase inhibitor NaSSA, noradrenergic and specific serotonergic antidepressant NDRI, norepinephrine and dopamine reuptake inhibitor SARI, serotonin antagonist and reuptake inhibitor SNRI, serotonin and norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

Different types of antidepressants are supposed to work by different means. SSRIs (selective serotonin reuptake inhibitors) are supposed to increase serotonin levels. NDRIs (norepinephrine dopamine reuptake inhibitors) are supposed to increase norepinephrine and dopamine, rather than serotonin. These two types of antidepressants are supposed to be selective , affecting the... 

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. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Serretti A, Zanardi R, Cusin C, et al (2001 a) No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors. Psychiatry Res 104 195-203... 

Amineptine, which is available as an antidepressant in some countries in Europe, is a selective dopamine reuptake inhibitor. Amineptine is an old drug and was not subjected to the rigorous trial methodology applied to more recent antidepressants. There are suggestions that amineptine may be associated with early onset of antidepressant action, but this has not been thoroughly studied (Garattini 1997). Some concerns have been expressed that amineptine may be associated with abuse potential, and theoretically these two phenomena may be linked through the dopamine system because of an amphetamine-like effect. 

A growing number of drugs are used that affect the many neurotransmitters in the brain benzodiazepines and others act on GABAergic transmission antidepressants, such as monoamine oxidase inhibitors and tricyclic antidepressants, are thought to increase the concentration of transmitter amines in the brain and so elevate mood—these will also act at peripheral nerve terminals, so interactions with them are a combination of peripheral and central actions. Levodopa (L-dopa) increases central as well as peripheral dopamine, and the newer class of psychoactive drugs, the selective serotonin reuptake inhibitors (SSRIs) of which the ubiquitous fluoxetine (Prozac) is best known, act in a similar way on serotonergic pathways. 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

Rasagiline Inhibits MAO-B selectively, higher doses also inhibit MAO-A Increases dopamine stores in neurons may have neuroprotective effects Parkinson s disease adjunctive to levodopa smooths levodopa response Oral Toxicity interactions may cause serotonin syndrome with meperidine, and theoretically also with selective serotonin reuptake inhibitors, tricyclic antidepressants... 

Long after their antidepressant properties were observed, the tricyclics were discovered to block the reuptake pumps for both serotonin and norepinephrine, and to a lesser extent, dopamine (Figs. 5 — 16, 6—5, and 6—6). Some tricyclics have more potency for inhibition of the serotonin reuptake pump (e.g., clomipramine) others are more selective for norepinephrine over serotonin (e.g., desipramine, maprotilene, nortriptyline, protriptyline). Most, however, block both serotonin and norepinephrine reuptake. 

The physiological action of antidepressants is not fully understood. However, they are thought to influence the metabolism, reuptake, or selective receptor antagonism of the neurotransmitters serotonin and norepinephrine. The MAOIs cause an increase of the neurotransmitters norepinephrine, serotonin, and dopamine in the brain by inhibiting their breakdown. The SSRIs prevent the reabsorbtion of serotonin, one of the 50-odd neurotransmitters in the brain. 

We know that dopamine deficiency is the cause of parkinsonism and that many RBD patients will develop this condition. Beyond that, it is not clear what is going on, although it is clear that prolonged use of a group of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs) can lead to RBD. This suggests that serotonin, which is known to be a potent inhibitor of REM, may interact with brain dopamine systems and upset the balance between inhibition and excitation of the motor systems in sleep. 

Amineptine is a tricyclic antidepressant that selectively reduces the dopamine reuptake without affecting the uptake of noradrenaline or serotonin (5-HT) (1). In vivo, it increases striatal homovanillic acid concentrations without affecting the concentrations of other metabolites of dopamine, 3,4,dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine. However, high doses of amineptine reduced the extracellular DOPAC concentration in the nucleus accumbens but not in the striatum. Long-term treatment with amineptine causes down-regulation of beta-adrenoceptors. 

This herb is also known as St. Joan s wort, klamath weed, and goatweed. It has historically been used for many purposes, but most recently it is marketed as an antidepressant. In fact, it outsells all conventional antidepressants in Germany. The active constituent is hypericin that seems to act as a weak monoamine oxidase MAO inhibitor and a selective serotonin reuptake inhibitor (SSRI). Dopamine and norepinephrine uptakes are also mildly inhibited. St. John s wort is available in many forms, as a tablet, tea, tincture, and the raw dried herb. For best results, a tablet standardized to contain 0.3% hypericin should be taken Kira by Lichtwer Pharma is the most extensively studied. Randomized, placebo-controlled trials using 300 mg of St. John s Wort three times daily have found it to be superior to placebo in mild to moderate depression. Response rates are generally regarded as inferior to conventional antidepressants, including... 

This diverse collection has been grouped together mostly because they do not operate as selective serotonin reuptake inhibitors. Instead, each one interacts differently with neurotransmitters that are tied to depression serotonin, norepinephrine, or dopamine. For instance, one of the more popular non-SSRIs, Effexor (venlafaxine), selectively inhibits the uptake of serotonin and norepinephrine, acting on the same molecular machinery as tricyclic antidepressants (TCAs). But, in contrast to TCAs, Effexor shows no affinity for other neurotransmitter receptors and thus has far fewer side effects than the... 

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