Neurotransmitters presynaptic serotonin

Human HRS encoded by a gene, which consists of four exons on chromosome 20, was demonstrated in 1987 and cloned recently [17]. HRS has initially been identified in the central and peripheral nervous system as presynaptic receptors controlling the release of histamine and other neurotransmitters (dopamine, serotonin. 

INHIBITION OF NEUROTRANSMITTER RELEASE BY PRESYNAPTIC SEROTONIN HETERORECEPTORS... 

Cocaine inhibits the presynaptic reuptake of the neurotransmitters norepinehrine, serotonin, and dopamine at synaptic junctions. This results in increased concentrations in the synaptic cleft. Since norepinephrine acts within the sympathetic nervous system, increased sympathetic stimulation is produced. Physiological effects of this stimulation include tachycardia, vasoconstriction, mydriasis, and hyperthermia.3 CNS stimulation results in increased alertness, diminished appetite, and increased energy. The euphoria or psychological stimulation produced by cocaine is thought to be related to the inhibition of serotonin and dopamine reuptake. Cocaine also acts as a local anesthetic due to its ability to block sodium channels in neuronal cells.3... 

However, the exact problem in CNS amine neurotransmission remains a subject of much debate. One leading theory is that depression may be caused by an increased sensitivity of the presynaptic or postsynaptic receptors for these transmitters. That is, the neurochemistry of the brain has been changed in some way to make the amine receptors more sensitive to their respective amine neurotransmitters (norepinephrine, serotonin, and to a lesser extent, dopamine).21 This theory is based primarily on the finding that antidepressant drugs prolong the activity of amine neurotransmission in the brain, thereby causing a compensatory decrease in the sensitivity of the amine receptors.21,47... 

If presynaptic histamine receptors are more uniform than presynaptic dopamine receptors, the contrary holds true for presynaptic serotonin receptors they are even more diverse than presynaptic dopamine receptors. As mentioned in the Introduction, presynaptic 5-HT3 receptors, being ligand-gated ion channels, are covered in the chapter by Dorostkar and Boehm and will be mentioned here only occasionally. Presynaptic G protein-coupled 5-HT receptors inhibit the release of serotonin from serotonergic axon terminals and inhibit or enhance the release of other neurotransmitters (Table 4). 

How it works Blocks reuptake of neurotransmitters (norepinephrine, serotonin) at presynaptic membranes,... 

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). 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

Galantamine is a ChE inhibitor, which elevates acetylcholine in the cerebral cortex by slowing the degradation of acetylcholine.37 It also modulates the nicotinic acetylcholine receptors to increase acetylcholine from surviving presynaptic nerve terminals. In addition, it may increase glutamate and serotonin levels. The clinical benefit of action of these additional neurotransmitters is unknown. 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Against this backdrop, researchers reported evidence that iproniazid, the antitubercular drug that was to become the first antidepressant, might increase norepinephrine and serotonin levels in the brain. How did it have this effect Recall that some of the neurotransmitter molecules released by a neuron are destroyed by enzymes in the synaptic cleft between the sending presynaptic neuron and the receiving postsynaptic neuron. When the neurotransmitter is a monoamine - like norepinephrine and serotonin - this process is called monoamine oxidase (MAO). As early as 1952 researchers at the Northwestern University Medical School in Chicago reported that iproniazid inhibited the oxidation of monoamines. This meant that iproniazid was a... 

The answer is that there are two ways in which neurotransmitter levels might be increased. One is to inhibit their destruction after they have been released into the synaptic gap. That is how MAOIs are supposed to work. Recall, however, that after a neurotransmitter is released, some of its molecules are reabsorbed by the presynaptic neuron that released them in a process that is called reuptake . Blocking this reuptake process should also increase the level of neuro transmitters in the brain. In 1961, Julius Axelrod, who later received the Nobel Prize in Medicine for his work on the release and reuptake of neurotransmitters, reported that imipramine, as well as a few other drugs, inhibited the reuptake of norepinephrine in cats. Two years later he reported that these drugs also inhibited the reuptake of serotonin.13... 

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. 

In neurochemical terms, amphetamine and cocaine boost monoamine activity. Amphetamine has a threefold mode of action first, it causes dopamine and noradrenaline to leak into the synaptic cleft second, it boosts the amount of transmitter released during an action potential and third, it inhibits the reuptake of neurotransmitter back into presynaptic vesicles. These three modes all result in more neurotransmitter being available at the synapse, thus generating an increase in postsynaptic stimulation. Cocaine exerts a similar overall effect, but mainly by reuptake inhibition. The main neurotransmitters affected are dopamine and noradrenaline, although serotonin is boosted to a lesser extent. These modes of action are outlined in Chapter 3, and the neurochemical rationale for drug tolerance is covered more fully in Chapter 10. The main differences between amphetamine and cocaine are their administration routes (summarised above) and the more rapid onset and shorter duration of action for cocaine. 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

Neurotransmitten Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic deft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic add, substance P, enkephalins, endorphins, and serotonin. [EU]... 

Several of the neurotransmitters are small-molecule amines such as dopamine, serotonin, epinephrine, and norepinephrine. These neurotransmitters are synthesized in the cytoplasm of the axon terminal and subsequently transported into and stored within the synaptic vesicles. The amino acids glycine and glutamic acid are normal constituents of proteins and are present in abundance in the axons. These are also stored in synaptic vesicles. Each electrical impulse that arrives at the presynaptic side of a synapse will cause only a small minority of the synaptic vesicles to fuse with the plasma membrane and discharge their contents. The remaining synaptic vesicles remain, waiting for subsequent electrical impulses. At the same time, neurotransmitter synthesis continues, as does their storage in synaptic vesicles. This tends to restore the full complement of amine neurotransmitters at the axon terminal. 

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 sensory neuron from the tail makes a synapse with the modulating neuron, known as an intemeuron. Its job is to fine-tune the response of the sensory neuron to stimulation. Note that the intemeuron synapses with both the cell body and the presynaptic terminal of the sensory neuron. The neurotransmitter released by the intemeuron into these synapses is serotonin (also a key neurotransmitter in the human nervous system). The net effect of the serotonin release is to strengthen the connection between the sensory neuron and the motor neuron. It remains to explain how this happens that, too, has been tracked down in molecular detail. 

It should be possible to treat the disease by increasing the concentration of the neurotransmitter in the synaptic cleft. There are, in principle, three ways in which this could be achieved, (i) Neurotransmitter synthesis could be increased, (ii) The rate of exocytosis could be increased, (iii) Removal of neurotransmitter from the synapse could be inhibited. Drugs that affect process (iii) have been developed. The tricyclic antidepressants and the specific serotonin (5-hydroxytryptamine) reuptake inhibitors (abbreviated to SSRIs) inhibit uptake of the neurotransmitter into the presynaptic on postsynaptic neurone. The most prescribed SSRI is fluoxetine (Prozac). 

Mechanism of Action A selective serotonin reuptake inhibitor that blocks the uptake of the neurotransmitter serotonin at CNS presynaptic neuronal membranes, increasing its availability at postsynaptic receptor sites. Therapeutic Effect Relieves depression. 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neurotransmitters, such as norepinephrine and serotonin, at CNS presynaptic membranes, increasing their availability at postsynaptic receptor sites. Therapeutic Effect Reduces obsessive-compulsive behavior. 

Mechanism of Action Atricyclicantidepressant, antineuralgic, andantineuriticagent that blocks the reuptake of neurotransmitters, such as norepinephrine and serotonin, at presynaptic membranes, increasing their concentration at postsynaptic receptor sites. Therapeutic Effect Relieves depression and controls nocturnal enuresis. Pharmacokinetics Rapidly, well absorbed following PO administration. Protein binding more than 90%. Metabolized in liver, with first-pass effect. Excreted in urine as metabolites. Half-life 6-18 hr. 

Tricyclic antidepressants (TCAs) modulate various brain neurotransmitters, especially norepinephrine and serotonin, by blocking reuptake presynaptically. The secondary amines (desipramine, nortriptyline) are more selective for noradrenergic function and have less side effects in sensitive populations. Advantages of this class of drugs include their relative long half life (approximately 12 hours), absence of abuse potential, and putative positive effects on mood and anxiety, sleep, and tics. 

These drugs seem to act on central 5-HT neurons in a manner that is not clear. They decrease the turnover of serotonin, possibly through a presynaptic receptor in the raphe cells. Since 5-HT is an inhibitory neurotransmitter in many of its actions, the removal of this inhibition could lead to behavioral changes. However, to discredit this simple hypothesis, there are a number of LSD derivatives that are not hallucinogens (e.g., the... 

In addition to serotonin, reserpine also releases other neurotransmitters, especially dopamine and noradrenaline, from their stores in presynaptic nerve raidings. Furthermore, the action on the synapse of the neurotransmitters released in this way is limited because they undergo intracellular enzymatic degradation. 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

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