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Josh-D. S. Davis

Xaminmo / Omnimax / Max Omni / Mad Scientist / Midnight Shadow / Radiation Master

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Excitotoxin
Josh 201604 KWP
joshdavis
Glutamate is the most common neurotransmitter in the brain. It is always excitatory, usually due to simple receptors that increase the flow of positive ions by opening ion-channels. Glutamate stimulation is terminated by a (chloride-independent) membrane transport system that is only used for re-absorbing glutamate & aspartate across the pre-synaptic membrane. Not all glutamate receptors are so simple, however.

Possibly the most complicated of all neurotransmitter receptors is the NMDA glutamate receptor. N-Methyl-D-Aspartate is a synthetic chemical not naturally found in biological systems, but it binds specifically to the NMDA glutamate receptor (receptors are frequently named for artificial substances that bind to the receptor with higher specificity than their natural neurotransmitter ligands). The NMDA receptor is the only known receptor which is regulated both by a ligand (glutamate) and by voltage. There are at least 5 binding sites which regulate NMDA receptor activity, ie, sites for (1) glutamate (2) glycine (3) magnesium (4) zinc and (5) a site that binds the hallucinogenic substance phencyclidine (PCP, "angel dust"). Phencyclidine can induce psychosis -- an NMDA effect that is difficult to explain. NMDA receptors have a capacity for an activity-dependent increase in synaptic efficiency known as LTP (Long-Term Potentiation), which may be crucial to some forms of learning & memory. Inhibition of NMDA activity (and LTP) is believed to be an important part of the way ethanol affects brain functions.

NMDA receptors are most densely concentrated in the cerebral cortex (hippocampus, especially -- particularly the CA1 region), amygdala, & basal ganglia. They are particularly vulnerable to glutamic acid excitotoxicity, ie, damaging effects due to excessive excitatory neurotransmitter release. Both aspartic acid & glutamic acid (the two amino acids having 2 carboxyl groups -- the "acidic amino acids") have the capacity for destroying neurons when released in excessive amounts (although calcium seems to be more of a cause than acidity). Monosodium glutamate (MSG), a major component of soya sauce, has been shown to destroy nerve cells when fed to young animals. Insofar as glutamate does not normally cross the blood-brain barrier, it is open to question whether this is relevant to a human adult. Increased alertness (or anxiety) due to caffeine may be mainly due to blockage of adenosine receptors which normally inhibit glutamate release.

Glutamate released into synapses is normally soaked-up by astrocytes (glial cells) which convert the glutamate into glutamine, a molecule which cannot cause excitotoxicity. The glutamine can then be safely transported back to neurons for re-conversion into glutamate. One of the damaging effects of mercury poisoning is swelling of astrocytes, which are rendered unable to soak-up glutamine from synapses (contributing to excitotoxicity). Excitotoxicity due to glutamic acid is a major destructive process seen in stokes and other forms of brain ischemia.


http://www.benbest.com/health/caffeine.html#adenosine
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