Serotonin transporter monoamine transporters

The pharmacology of amphetamine is considerably more complex. It does not only block monoamine reuptake, but also directly inhibits the vesicular monoamine transporter, causing an increase in cytosolic but not vesicular dopamine concentration. This may lead to reverse transport of the amines via the membrane-bound transporters. Further mechanisms of amphetamine action are direct MAO inhibition and indirect release of both dopamine and serotonin in the striatum. 

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

The affinity (Kj values) observed for [ H]MDA and [ HJMDMA binding were similar to the effective doses (i.e., ED50 or K] values) of MDA and MDMA reported for various pre- and postsynaptic monoamine markers, such as serotonin and dopamine release (Johnson et al. 1986), monoamine transport (Steele et al. 1987), and multiple brain, ligand binding sites (Battaglia et al. 1988). 

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. 

Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants. By interacting with these transporters (Chs 12 and 13), psychomotor stimulants increase extracellular levels of monoamine neurotransmitters. Cocaine is a monoamine uptake inhibitor. The reinforcing effects of cocaine correlate best with its binding potency at the DAT. However, experiments with monoamine transporter-deficient mice suggest that cocaine actions at... 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK (1999) Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 88 61-66 Hahn MK, Blakely RD (2002) Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenomics J 2 217-235 HeUs A, Teufel A, Petri S, et al (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66 2621-2624... 

Dahlstrom, M., Ahonen, A., Ebeling, H., Torniainen, P., Heikkila, J., and Moilanen, I. (2000) Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents. Mol Psychiatry 5 514—522. 

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

Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). and C show the effects of amphetamine and cocaine on these pathways. See text for details. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

HTxR, serotonin receptor CB1R, cannabinoid-1 DAT, dopamine transporter GABA, y-aminobutyric acid Kir3 channels, G protein-coupled inwardly rectifying potassium channels LSD, lysergic acid diethylamide i -OR, H-opioid receptor nAChR, nicotinic acetylcholine receptor NET, norepinephrine transporter NMDAR, N -methyl-D-aspartate receptor SERT, serotonin transporter VMAT, vesicular monoamine transporter indicates data not available. 

FIGURE 5—35. Serotonin is destroyed by the enzyme monoamine oxidase (MAO) and converted into an inactive metabolite. The 5HT neuron has a presynaptic transport pump selective for serotonin, which is called the serotonin transporter and is analogous to the norepinephrine (NE) transporter in NE neurons (Fig. 5-18) and to the DA transporter in DA neurons (Fig. 5-32). 

Glutamate removal. Glutamate s actions ate stopped not by enzymatic breakdown, as in other neurotransmitter systems, but by removal by two transport pumps. The first of these pumps is a presynaptic glutamate transporter, which works as do all the other neurotransmitter transporters already discussed for monoamine neurotransmitter systems such as dopamine, norepinephrine, and serotonin. The second transport pump, located on nearby glia, removes glutamate from the synapse and terminates its actions there. Glutamate removal is summarized in Figure 10—22. 

Cocaine (Fig. 13—3) has two major properties it is both a local anesthetic and an inhibitor of monoamine transporters, especially dopamine (Fig. 13—4). Cocaine s local anesthetic properties are still used in medicine, especially by ear, nose, and throat specialists (otolaryngologists). Freud himself exploited this property of cocaine to help dull the pain of his tongue cancer. He may have also exploited the second property of the drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of dopamine reuptake at the dopamine transporter. Cocaine also has similar but less important actions at the norepinephrine and the serotonin transporters (Fig. 13—3). Cocaine may do more than merely block the transporter—it may actually release dopamine (or norepinephrine or serotonin) by reversing neurotransmitter out of the presynaptic neuron via the monoamine transporters (Fig. 13—4). 

Amphetamine s primary effects (increased wakefulness, appetite suppression, and increased locomotor activity) are thought to be mediated by the release of norepinephrine from noradrenergic neurons in the CNS (36). However, research points to the role of plasma transport inhibition of dopamine, norepinephrine, and serotonin as well as inhibition of the vesicular monoamine transporter (138). Wisor et al. (139) summarize evidence that dopamine reuptake inhibition produces a greater alerting effect than norepinephrine transport blockade. 

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