Dopamine-selective reuptake

Pharmacology These agents are potent and selective inhibitors of neuronal serotonin reuptake and they also have a weak effect on norepinephrine and dopamine neuronal reuptake. 

Reboxetine is a norepinephrine selective reuptake inhibitor (NSRI). Based on in vitro studies, reboxetine does not block the reuptake of either dopamine or serotonin. 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

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). 

As with other monoamines, the actions of 5-HT are terminated by its reuptake from the synapse by another member of the family of Na+/CU-dependent transporters. The 5-HT transporter has many features in common with its catecholamine equivalent (described fully in Chapter 8 see Fig. 8.7), including its presumed 12 transmembrane-spanning domains. However, the cloned 5-HT transporter has a for 5-HT of about 450 nM whereas its K for both noradrenaline and dopamine is some ten thousand-fold greater (Povlock and Amara 1997) which means that it is relatively selective for uptake... 

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. 

Slow-onset, long duration dopamine reuptake inhibitors with reduced potential for substance abuse have been suggested as therapies for psychostimulant addiction [33-35]. A series of slow-onset, long duration N-alkyl analogues of methylphenidate were recently reported to have enhanced selectivity for the dopamine transporter [34]. A representative compound is 13, an RR/SS diastereomer (DAT K, = 16nM, SERT K = 5900 nM, NET K-, = 840 nM). In a locomotor activity assay in mice, 13 has a slow onset of activity (20-30 min) with peak activity occurring between 90 and 120 min. In contrast, both methylphenidate and cocaine are active within 10 min and reach peak activity within 30 min. 

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. 

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. 

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... 

Clear abnormalities of the dopamine system have not been identified in the periphery or the brain of OCD patients. Nevertheless, repetitive stereotypies and OCD-like behaviors can be produced in humans by the administration of exogenous D2 agonist or stimulants, which suggests that the dopaminergic system may be involved in some way in OCD. Conversely, antipsy-chotics can be used adjunctively in the treatment of selective serotonin reuptake inhibitor (SSRl)-resistant OCD patients with a definite benefit in a significant proportion of patients. 

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. 

---