Presynaptic vesicles

Salin-Pascual, R. J. Jimenez-Anguiano, A (1995). Vesamicol, an acetylcholine uptake blocker in presynaptic vesicles, suppresses rapid eye movement (REM) sleep in the rat. Psychopharmacology, fieri. 121, 485-7. 

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. 

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 84 Packaging neurotransmitters into presynaptic vesicles is mediated by proton-coupled antiporters 86... 

Presynaptic vesicles are estimated to each contain approximately 3,000-5,000 transmitter molecules the internal volume of a vesicle is such that its internal transmitter concentration may be =0.5 mol/1 vesicle contents may be released within less than 1 ms and this occurs within <0.02 pm of the postsynaptic receptors. The space within... 

One of the consequences of this rapid increase in protein synthetic capacity in VMN neurons is that E increases the number of spines on dendrites and increases the density of synapses in the VMN. These events occur cyclically during the estrous cycle of the female rat. Dots indicate presynaptic vesicles containing neurotransmitter. 

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. 

As was mentioned before, neurotransmitters are synthesized within the neuron either in the cell body or in the synaptic area and stored in presynaptic vesicles. 

Storage of neurotransmitter. A certain amount of chemical transmitter is stored in presynaptic vesicles. Drugs that impair this storage will decrease the ability of the synapse to continue to transmit information for extended periods. 

An example of this is the antihypertensive drug reserpine (Serpalan, Serpasil), which impairs the ability of adrenergic terminals to sequester and store norepinephrine in presynaptic vesicles. 

Mechanism of action. The cellular actions of bot-ulinum toxin at the neuromuscular junction have recently been clarified.84 This toxin is attracted to glycoproteins located on the surface of the presynaptic terminal at the skeletal neuromuscular junction.33 Once attached to the membrane, the toxin enters the presynaptic terminal and inhibits proteins that are needed for acetylcholine release (Figure 13-4).84 Normally, certain proteins help fuse presynaptic vesicles with the inner surface of the presynaptic terminal, thereby allowing the vesicles to release acetylcholine via exocytosis. Botulinum toxin cleaves and destroys these fusion proteins, thus making it impossible for the neuron to release acetylcholine into the synaptic cleft.32,84 Local injection of botulinum toxin into specific muscles will therefore decrease muscle excitation by disrupting synaptic transmission at the neuromuscular junction. The affected muscle will invariably undergo some degree of paresis and subsequent... 

Anti-amphiphysin Amphiphysin Presynaptic vesicles Stiff-Person syndrome Breast, SCLC... 

Other presynaptic elements, such as complexins, that dock presynaptic vesicles (Brose, 2008) or syanptotagmin, which may couple Ca2+ entry to rapid vesicle fusion, permitting synchronous presynaptic glutamate release (Maximov and Sudhof, 2005), have not been heavily investigated in schizophrenia. One study has suggested an abnormal interaction between complexin-2 and synapsin-2 in schizophrenia, illustrating the complexity of the potential dysfunctional mechanisms (Lee et al., 2005). 

If you have followed closely what has been said before, you might now be wondering why dopamine should be too polar to cross the membranes that represent the blood brain barrier, but should readily cross those of the presynaptic vesicles. The answer to this apparent paradox (aside from the fact that the blood brain barrier actually consists of four membranes in series) lies in the vastly different surface-to-volume ratios of the two compartments. Think of a pinhole in a thimble vs. one in a swimming pool. 

In dopaminergic neurons, dopamine is not metabolized further but is stored in presynaptic vesicles. In noradren-... 

Winter HC, Ueda T (1993) Glutamate uptake system in the presynaptic vesicle glutamic acid analogs as inhibitors and alternate substrates. Neurochem Res 78 79-85. 

Wiedenmann B, Franke WW. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 3 8,000 characteristic of presynaptic vesicles. Cell. 1985 41 1017-1028. 

This is a selective a2-adrenergic agonist that suppresses the release of norepinephrine from presynaptic vesicles into the synaptic cleft, thus reducing its concentration, with a consequent improvement in akathisia. 

Peripheral presynaptic anti-adrenergics inhibit norepinephrine release from the presynaptic terminal. Guanadrel and reserpine deplete norepinephrine from presynaptic vesicles. As a result, guanadrel initially releases norepinephrine from the terminal causing a transient increase in adrenergic transmission. 

Reserpine (e.g., Sandril) Depletes catecholamines and serotonin in brain, adrenal, and heart. Inhibits uptake of norepinephrine into presynaptic vesicles. Chronically sensitizes patient to sympathomimetics. Gradual 4 mean arterial pressure with bradycardia. Antihypertensive effects due to 4 cardiac output. Tranquilization, sedation. Nightmares, depression, diarrhea, cramps, T risk of breast cancer, peptic ulcers, parasympathetic predominance. 

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