Presynaptic neuronal membrane

G -protein-coupled receptors are often located on the presynaptic plasma membrane where they inhibit neurotransmitter release by reducing the opening of Ca2+ channels like inactivation and breakdown of the neurotransmitter by enzymes, this contributes to the neuron s ability to produce a sharply timed signal. An a2 receptor located on the presynaptic membrane of a noradrenaline-containing neuron is called an autoreceptor but, if located on any other type of presynaptic neuronal membrane (e.g., a 5-HT neuron), then it is referred to as a heteroreceptor (Langer, 1997). Autoreceptors are also located on the soma (cell body) and dendrites of the neuron for example, somatodendritic 5-HTia receptors reduce the electrical activity of 5-HT neurons. 

Presynaptic receptor A receptor, either an autoreceptor or heteroreceptor, located on the presynaptic neuronal membrane which regulates the release of the neurotransmitter. 

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 tetracyclic compound that blocks reuptake norepi nephri ne by CNS presynaptic neuronal membranes, increasing availability at postsynaptic neuronal receptor sites, and enhances synaptic activity. Therapeutic Effect Produces antidepressant effect, with prominent sedative effects and low anticholinergic activity. Pharmacokinetics Slowly and completely absorbed after PO administration. Protein binding 88%. Metabolized in liver by hydroxylation and oxidative modification. Excreted in urine. Unknown if removed by hemodialysis. Half-life 27-58 hr. 

It is phenyltriazine compound, chemically unrelated to existing antiepileptic drugs. It acts primarily via a dose dependent blockade of voltage sensitive sodium channels in their slow inactivated state, thus stabilizing the presynaptic neuronal membrane inhibiting release of excitatory neurotransmitters mainly glutamate. 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

Lamotrigine acts to stabilise presynaptic neuronal membranes by blocking voltage-dependent sodium channels (a property it shares with carbamazepine and phenytoin) and it reduces the release of excitatory amino acids, such as glutamate and aspartate. The t/ of 24 h allows for a single daily dose. 

Lamotrigine (Lamigtal) was originally synthesized as a dihydrofolate reductase inhibitor. The compound was much better as an epileptic than it was in its original mission. Its talent is apparently in stabilizing presynaptic neuronal membranes by blocking their sodium channels as well as inhibiting excitory neurotransmitters. These features make it useful in the treatment of partial onset epilepsy. 

Imipramine is a 10,11 -dihydrodibenzazepine tertiary amine TCA (Fig. 21.15) that is marketed as hydrochloride and pamoate salts, both of which are administered orally. Although the hydrochloride salt may be administered in divided daily doses, imipramine s long duration of action suggests that the entire oral daily dose may be administered at one time. On the other hand, imipramine pamoate usually is administered as a single daily oral dose. Imipramine preferentially inhibits 5-HT reuptake over NE however, the formation of its N-desmethyl metabolite removes whatever 5-HT activity imipramine had, with the net result of enhanced noradrenergic activity from inhibition of NE reuptake at the presynaptic neuronal membrane. Imipramine shares the pharmacological and adverse-effect profile of the other tertiary TCAs. 

Clomipramine is different from the other TCAs, exhibiting preferential selectivity for inhibiting the reuptake of 5-HT at the presynaptic neuronal membrane. Its antidepressant mechanism of action as an inhibitor of the 5-HT transporter is reduced in vivo, however, because of the formation of its active metabolite, N-desmethylclomipramine, which inhibits the reuptake of NE. As a result of its common structure with the other TCAs, clomipramine shares the pharmacological and adverse-effect profile of the other TCAs. 

The efficacy of clomipramine relative to the other TCAs in the treatment of obsessive-compulsive disorder may be related to its potency in blocking 5-HT reuptake at the presynaptic neuronal membrane, suggesting a dysregulation of 5-HT for the pathogenesis of obsessive-compulsive disorder. Clomipramine appears to decrease the turnover of 5-HT in the CNS, probably because of a decrease in the release and/or synthesis of 5-HT. 

Although the mechanism of antidepressant action for bupropion is unclear, in vitro binding studies show bupropion to be a selective inhibitor of dopamine reuptake at the dopamine presynaptic neuronal membrane and minimal inhibition of NE and 5-HT reuptake (Table 21.2). Bupropion does not exhibit clinically significant anticholinergic, antihistaminic, ai-adrenergic blocking activity, or MAO inhibition. 

Unbound synaptic neurotransmitters, such as DA, 5-HT, NE, and others are taken back into the neuron by binding to protein transporters on the presynaptic neuronal membranes, which remove neurotransmitters from the synaptic cleft. Neurotransmitters also are inactivated by enzymatic degradation. 

A neuron, or nerve cell, is an example of an excitable cell. These cells have cell bodies (or soma) containing the nucleus and elongated processes called axons and dendrites. These cells form a complex web with many connections. Figure 11 shows a schematic diagram of a connection between two such nerve cells. The presynaptic neuron is separated from the postsynaptic neuron by a small gap known as the synapse, typically 2-800 A wide. Presynaptic nerve endings contain small sacs or vesicles filled with one of several compounds called neurotransmitters. The postsynaptic neuron has receptor sites for specific neurotransmitters located on the cell membrane. When appropriately stimulated, and area of a presynaptic neuron membrane becomes depolarized (the transmembrane potential becomes more positive). The depolarized area propagates down the axon very rapidly. This wave-like movement of depolarization is called the action potential. When the depolarized areas reaches the nerve ending, the vesicles move to the cell wall, fuse with it, and dump their contents into the synaptic cleft—a process called exocytosis. (Exocytosis is accepted as the mechanism of neurotransmitter release in the peripheral nervous system, but it has not yet been demonstrated... 

Temporal summation occurs when multiple EPSPs (or IPSPs) produced by a single presynaptic neuron in close sequence exert their effect on membrane potential of the postsynaptic neuron. For example, an action potential in the presynaptic neuron produces an EPSP and partial depolarization of the postsynaptic neuron (see Figure 5.2). While the postsynaptic neuron is still depolarized, a second action potential in the presynaptic neuron produces another EPSP in the postsynaptic neuron that adds to the first and further depolarizes this neuron. 

As more EPSPs add together, the membrane depolarizes closer to threshold until an action potential is generated. Although temporal summation is illustrated in Figure 5.2 with the summation of relatively few EPSPs, in actuality, addition of up to 50 EPSPs may be necessary to reach threshold. Because a presynaptic neuron may generate up to 500 action potentials per... 

Figure 5.3 Spatial summation. Multiple excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs) produced by many presynaptic neurons simultaneously may add together to alter the membrane potential of the postsynaptic neuron. Sufficient excitatory input (A and B) will depolarize the membrane to threshold and generate an action potential. The simultaneous arrival of excitatory and inhibitory inputs (A and C) may cancel each other out so that the membrane potential does not change.

Following the release of dopamine, the primary mode of removal from the synapse is reuptake into the presynaptic neuron via the dopamine transporter (DAT). DAT is dependent upon the energy created by the Na+/K+ pump and is a member of the Na+/Cl -dependent plasma membrane transporter family, as are the norepinephrine and 7-aminobutyric acid (GABA) transporters. Imaging studies utilizing compounds with highly specific affinity for DAT... 

Figure 1.1 The dopamine transporter terminates the action of released dopamine by transport back into the presynaptic neuron. Dopamine transport occurs with the binding of one molecule of dopamine, one chloride ion, and two sodium ions to the transporter the transporter then translocates from the outside of the neuronal membrane into the inside of the neuron.22 Cocaine appears to bind to the sodium ion binding site. This changes the conformation of the chloride ion binding site thus dopamine transport does not occur. This blockade of dopamine transport potentiates dopaminergic neurotransmission and may be the basis for the rewarding effects of cocaine.

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. 

Inside the cytoplasm of the presynaptic neuron the monoamines are exposed to the mitochondrial outer membrane-bound enzyme monoamine oxidase (MAO). MAO breaks the monoamines down into inactive metabolites before they are taken up into the vesicles. However, if MAO is inhibited, then the monoamines enter the vesicles and are available for release. MAO inhibitors, such as moclobemide, have been used in the treatment of depression, since they increase the availability of noradrenaline and serotonin. Selegiline is used for Parkinson s disease, since it raises dopamine levels. 

Synapse The area where two neurons meet. It includes the presynaptic neuronal terminal plasma membrane of one neuron and the postsynaptic membrane of another neuron. More specifically, it refers to the space or gap between them, often called the synaptic cleft. 

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 first step is the synthesis of the enzymes that are involved in the formation of the neurotransmitters, which occurs on the rough endoplasmic reticulum in the cell body. They are then transferred to the terminus of the presynaptic neurone by axonal transport. Here the neurotransmitters are synthesized prior to packaging into vesicles. The contents of the vesicles are, upon stimulation of the presynaptic neurone, released into the synaptic cleft. After binding to the postsynaptic receptor they are inactivated either by uptake from the cleft back into the presynaptic neurone or by enzymic degradation (Figure 14.9). After exocytosis, the membrane of the vesicle can be recycled back into the presynaptic neurone for re-filling and further exocytosis (see Figure 14.8). 

Figure 14.8 Simple diagram of release of neurotransmitter and recycling of the vesicles in presynaptic neurone. After exocytosis, the membrane recycles to form a new vesicle which is re-filled with neurotransmitter. The Ca ion binding protein may control packaging, formation of fusion pore and release of neurotransmitter.

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

The activation a2-adrenoceptors is particularly important in the negative feedback control of adrenergic outflow, centrally in the vasomotor centers and peripherally at the presynaptic axonal membrane of adrenergic neurons. 

Mechanism of Action An anticonvulsant whose exact mechanism is unknown. May block voltage-sensitive sodium channels, thus stabilizing neuronal membranes and regulating presynaptic transmitter release of excitatory amino acids. Therapeutic Effect Reduces seizure activity... 

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