Neurotransmitters neurotransmitter reuptake

GABA transporter GAT1 (SLC6A1) GABAergic neurons in CNS <10 Clearance of interstitial neurotransmitter, reuptake into neurons Tiagabine, an antiepileptic drug... 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced. 

The recovery of neurotransmitters from synaptic clefts and their storage in cytoplasmic vesicles is accomplished by the tandem actions of the secondary transporters in plasma and vesicular membranes. Sodium-dependent symporters mediate neurotransmitter reuptake from synaptic clefts into neurons and glia, whereas proton-dependent antiporters concentrate neurotransmitters from neuronal cytoplasm into synaptic vesicles (Fig. 5-13). 

While the extent of the demands on cerebral energy metabolism of neurotransmitter reuptake is still somewhat controversial, it contributes substantially to the... 

Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. (1998). Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychia y. 31(suppl 1) 16-21. 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

The principal mechanism for the deactivation of released catecholamines is, however, not enzymatic destmction but reuptake into the nerve ending. The presynaptic membrane contains an amine pump—a saturable, high-affinity, Na" -dependent active-transport system that requires energy for its function. The recycled neurotransmitter is capable of being released again, as experiments with radiolabelled [ H]NE have shown, and can be incorporated into chromaffin granules as well. Many drugs interfere with neurotransmitter reuptake and metabolism, as discussed in subsequent sections. 

Amphetamines not only mimic the action of norepinephrine and dopamine they also boost the levels of these neurotransmitters in a synaptic cleft by blocking their removal. Normally, neurotransmitters are reabsorbed by presynaptic neurons after they have exerted their effect on postsynaptic receptor sites. This process, commonly called neurotransmitter reuptake and illustrated in Figure 14.24, is the body s way of recycling neurotransmitters, molecules that are difficult to synthesize. Special membrane-embedded proteins are required to pull once-used neurotransmitter molecules back into a presynaptic neuron. Amphetamines inactivate norepinephrine and dopamine reuptake proteins by binding to them. As a consequence, the concentration of these stimulating neurotransmitters in the synaptic cleft is maintained at a higher-than-normal level. 

Was this your answer Amphetamines and cocaine in the synaptic cleft both mimic the action of neurotransmitters.They also block the reuptake of neurotransmitters, which results in an increase in the concentration of neurotransmitters in the cleft. The main action of amphetamines is their mimicking of neurotransmitters, whereas the main action of cocaine is the blocking of neurotransmitter reuptake. 

Neurotransmitter reuptake A mechanism whereby a presynaptic neuron absorbs neurotransmitters from the synaptic cleft for reuse. 

C. Neurotransmitter synaptic reuptake—an example of molecular transport using an active transport pump... 

Neurotransmitter Synaptic Reuptake—an Example of Molecular Transport Using an Active Transport Pump... 

FIGURE 2—20. The transport carrier for neurotransmitter reuptake is like a box car with reserved seats for molecules for neurotransmitter. Here the transport carrier is empty. Its tires are flat, and it is unable to transport neurotransmitter. 

FIGURE 2—21. The neurotransmitter reuptake transporter can bind neurotransmitter molecules at specific binding sites. Here the neurotransmitter is bound to transporter sites, ready for a trip inside the neuron. It is now binding the neurotransmitter serotonin (SHT) because it has found sodium ions, which have increased its affinity for serotonin, resulting in the tires being pumped up and full of air, ready for transport. 

An example of negative allosteric modulation is the case of the antidepressants, which act as neurotransmitter reuptake blockers for the neurotransmitters norepinephrine and serotonin. This has already been discussed in Chapter 2. When the neurotransmitters norepinephrine and serotonin bind to their own selective receptor sites, they are normally transported back into the presynaptic neuron, as shown in Figure 2-23- Thus the empty reuptake carrier (Fig. 2—20) binds to the neurotransmitter (Fig. 2—21) to begin the transport process (Fig. 2—23). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter (represented as an icon in Figs. 2—22 and 2—24), this causes the neurotransmitter to no longer be able to bind there, thereby blocking synaptic re-... 

An antidepressant drug, which blocks norepinephrine and serotonin reuptake, can be said to modulate in a negative allosteric manner the presynaptic neurotransmitter transporter and thereby block neurotransmitter reuptake (Figs. 2—22 and 2—24). As developed in detail in later chapters, this action may have therapeutic implications for a number of disorders, including depression, panic disorder, and obsessive-compulsive disorder. 

FIGURE 5—16. Tricyclic antidepressants exert their antidepressant action by blocking the neurotransmitter reuptake pump, thus causing neurotransmitter to accumulate. This accumulation, according to the monoamine hypothesis, reverses the prior neurotransmitter deficiency (see Fig. 5—14) and relieves depression by returning the monoamine neuron to the normal state. 

Desipramine is a tricyclic antidepressant that has been tested in several double-blind trials among cocaine addicts. Like cocaine, desipramine inhibits monoamine neurotransmitter reuptake, but its principal effects are on norepinephrine reuptake. It was hypothesized that desipramine could relieve some of the withdrawal symptoms of cocaine dependence and reduce the desire for cocaine during the vulnerable period following cessation of cocaine. This drug showed efficacy early in the epidemic in a group of patients who were primarily white collar intranasal cocaine users. The majority of subsequent studies of desipramine-using, more severely ill cocaine addicts have been negative. 

The principal groups of antidepressants available today are all presumed to exert their action via alteration of brain monoamine metabolism. These amines include norepinephrine, dopamine, and serotonin. The involvement of catecholamines in the pathogenesis of depression was invoked as early as 1965. A deficiency in brain serotonin was theorized in 1967, while a role for dopamine in depression was formally proposed in 1975. The drugs that are used to treat depression basically act to increase neurotransmitter concentration in the synaptic cleft either by (1) decreasing neurotransmitter degradation or (2) inhibiting neurotransmitter reuptake. 

Atomoxetine is the most recent neurotransmitter reuptake inhibitor to reach the market (Fig. 2.3). It is a selective inhibitor of norepinephrine (noradrenaline) transport, and during the 1980s was - as tomoxetine - evaluated clinically for the... 

Tramadol, however, is thousands of times less potent than morphine as an analgesic agent [18]. It is marketed in the racemic form, and each enantiomer has distinct pharmacological actions. The (+)-isomer is a weak MOP agonist, while the (-)-isomer inhibits neurotransmitter reuptake (norepinephrine and serotonin). The O-demethylated metabolite has improved opioid receptor affinity but is still much less potent (35-fold) than morphine. The ability for this metabolite to ameliorate the analgesic effects of tramadol has not been well studied and remains questionable. The drug has been used for decades in Europe, but was only recently introduced in the United States. It has a greater safety profile than morphine, and produces no respiratory depression or constipation. It is also claimed to be nonaddictive, but remains unscheduled. 

A related structural analog, (II), prepared by Richelson (2) was effective as a selective norepinephrine or epinephrine neurotransmitter reuptake inhibitor. 

Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN (2(X)7) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Sdence 317 1390-1393... 

Amara SG, Pacholczyk T (1991) Sodium-dependent neurotransmitter reuptake systems. Curr Opin Neurobiol 1 84-90... 

Neurotransmitter reuptake. A drug may block the reuptake of heurotransmitters into the axon terminals. 

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... 

Denervated effector tissues are nonresponsive because these drugs act either to release transmitter from nerve terminals or to inhibit neurotransmitter reuptake. 

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