Monoamine transporters neurotransmitters reuptake

The transporters for 5HT, noradrenaline and dopamine, biogenic monoamines, are genetically related, exist as single isoforms and are expressed on the surface of nerve cells, which use monoamines as (or convert them into) their cognate neurotransmitter. The single-isoform monoamine transporters fulfil all three fundamental functions (reuptake, limiting synaptic transmission, and control of the extracellular neurotransmitter concentration). Inactivation of DAT, NET, or SERT results in an increased extracellular lifetime and level of monoamine neurotransmitter, but decreased intracellular storage and evoked release (Fig. 3). 

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). 

Fig. 1 General model of the release of vesicular neurotransmitter stores in response to cellular depolarization and the reuptake of the neurotransmitters by the monoamine transporters. Cytosolic neurotransmitters are taken into vesicles by VMAT and stored until the cell becomes depolarized, causing these vesicular stores to fuse with the plasma membrane and release the neurotransmitters into the synaptic cleft. Neurotransmitters in the synaptic cleft are available to bind pre- or postsynaptic receptors. Termination of signaling occurs when the neurotransmitters are taken back into the presynaptic cell by the monoamine transporters...

Although plasma membrane monoamine transporters are responsible for the reuptake of neurotransmitters from the synapse, vesicular monoamine transporters (VMAT) sequester monoamines into synaptic vesicles in preparation for fusion with the plasma membrane and release into the synapse (Schuldiner et ah, 1995). Vesicular uptake is coupled to a proton gradient across the vesicle membrane rather than the sodium gradient used with the plasma membrane transporters (Schuldiner et ah, 1995). These vesicular transporters are not neurotransmitter-speciflc rather, they transport the monoamines nonselectively (Johnson, Jr., 1988 Henry et ah, 1998). 

Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-hydroxytryptamine (5-HT)], norepinephrine [NE noradrenaline (NA)], or both. They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a neurotransmitter receptor. Hence, the antidepressants can be classified on the basis of their putative mechanisms of action (Table 8.2 and Figs. 8.1-8.4). Agents that block neurotransmitter reuptake can be further divided into those that are non-selective (e.g., tricyclic antidepressants with mixed action), serotonin-selective reuptake... 

After release from storage sites in presynaptic monoamine transporter vesides, DA is bound by postsynaptic DA receptors, and unbound DA is broken down by enzymes, or taken back into presynaptic neurons, called reuptake into presynaptic neurons by spedfic presynaptic protein transporters. The uptake of neurotransmitters by presynaptic neurons is a major mechanism for stopping neurotransmission. The recyded neurotransmitter is repackaged in vesicles in presynaptic neurons, and then rdeased again in response to stimulation by presynaptic electrical action potentials. Tracers have been developed to assess the vesicular membranes, as well as the specific reuptake protein transporters. The selectivity with which monoaminergic neurons store DA, 5-HT, NER, or histamine in presynaptic vesides depends on the spedficity of the membrane transporters. 

Amphetamine and related substances show symphaticomimetic and CNS stimulant activity. Amphetamines are indirect monoamine agonists and interact with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. Therefore, they stimulate the release of norepinephrine, dopamine, and serotonin from presynaptic terminals in the CNS and at the peripheral level (De La Torre et al., 2004). Methamphetamine and the methylenedioxy derivatives (MDA, MDMA, MDEA, MBDB) can inhibit the activity of enzymes of dopamine or serotonin biosynthesis (De La Torre et al., 2004). 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

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. 

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). 

In an attempt to explain the reason for the delay in the onset of the therapeutic effect of antidepressants, which is clearly unrelated to the acute actions of these drugs on monoamine reuptake transporters or intracellular metabolizing enzymes, emphasis has moved away from the presynaptic mechanism governing the release of the monoamine transmitters to the adaptive changes that occur in pre- and postsynaptic receptors that govern the physiological expression of neurotransmitter function. 

The first antidepressants to be discovered came from two classes of agents, namely, the tricyclic antidepressants, so named because their chemical structure has three rings, and the MAO inhibitors, so named because they inhibit the enzyme MAO, which destroys monoamine neurotransmitters. When tricyclic antidepressants block the NE transporter, they increase the availability of NE in the synapse, since the vacuum cleaner reuptake pump can no longer sweep NE out of the synapse (Figs. 5—16 and 5—18). When tricyclic antidepressants block the DA pump (Fig. 5—32) or the 5HT pump (Fig. 5—35), they similarly enhance the synaptic availability of DA or 5HT, respectively, and by the same mechanism. When MAO inhibitors block NE, DA, and 5HT breakdown, they boost the levels of these neurotransmitters (Fig. 5-15). 

There are two principal mechanisms for increasing synaptic monoamine levels. One is to block the reuptake of neurotransmitter after its excitation-coupled release from the neuronal terminal. Thus, blocking the action of the uptake carrier protein prevents clearance of the neurotransmitter from the synapse, leaving high concentrations in the synaptic cleft that can continue to exert a signaling effect. This mechanism is the one invoked to explain the action of cocaine, a potent inhibitor of monoamine reuptake at the dopamine, serotonin, and norepinephrine transporters, and of methylphenidate, which is a reuptake inhibitor at the dopamine and norepinephrine transporters (81)It should be noted, however, that methylphenidate also has the ability to induce the release of catecholamines stored in neuronal vesicles (82, 83). 

The catecholamines epinephrine, norepinephrine, and dopamine are inactivated by oxidation reactions catalyzed by monoamine oxidase (MAO) (Figure 15.10). Because MAO is found within nerve endings, catecholamines must be transported out of the synaptic cleft before inactivation. (The process by which neurotransmitters are transported back into nerve cells so that they can be reused or degraded is referred to as reuptake.) Epinephrine, released as a hormone from the adrenal gland, is carried in the blood and is catabolized in nonneural tissue (perhaps the kidney). Catecholamines are also inactivated in methylation reactions catalyzed by catechol-O-methyltransferase (COMT). These two enzymes (MAO and COMT) work together to produce a large variety of oxidized and methylated metabolites of the catecholamines. 

Serotonin, also known as 5-hydroxytryptamine (5-HT) is biosynthesized from tryptophan and is a neurotransmitter. Serotonin plays an important role in many behaviors including sleep, appetite, memory, and mood [52]. People with depressive disorders exhibit low levels of serotonin in the synapses. Protonated serotonin binds to a serotonin reuptake transporter protein, sometimes referred to as the serotonin transporter (SERT) and is then moved to an inward position on the neuron and subsequently released into the cjdoplasm. Selective serotonin reuptake inhibitors (SSRI) bind with high affinity to the serotonin binding site of the transporter. This leads to antidepressant effects by increasing extracellular serotonin levels which in turn enhances serotonin neurotransmission [53]. The SSRI class of antidepressants has fewer side effects than the monoamine oxidase inhibitors. 

Psychostimulant pharmacology involves an augmented release of noradrenaline and dopamine into the synaptic cleft. The presence of monoamine neurotransmitters in the synaptic cleft is regulated in a variety of ways in response to an action potential. Around 70-80% of all transmitter molecules return into the presynaptic neuron by uptake using an energy-dependent reuptake transport protein that is embedded in the neuronal membrane. A smaller fraction... 

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