Excitatory amino acids (EAA) became known as neurotransmitters of the
central nervous system (CNS) in the last decade. The most studied EAA
are glutamate and aspartate. Both are synthetized by the same mechanis
m as gama-aminobutyric acid. (Fig. 1). Glutamate is widely distributed
in the CNS and the spinal cord, being the areas of higher concentrati
on the cerebral cortex, the hypocampus and the cerebellum. There have
been identified two type of receptors for glutamate: ionotropic and me
tabotropic. The former includes three different types: NMDA, AMPA and
KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the secon
d ion the most important one. This receptor has several sites of bindi
ng for various substances. Along with the site for N-methyl-D-aspartat
e, which binds glutamate and/or aspartate, there have been identified
a site for the binding of glycine (which is different from the strychn
ine sensitive one), a site for pollamines such as spermine and spermid
ine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is as
sociated to a Ca2+-Na+ channel, being in this case the Na+ the most im
portant ion. There are two metabotropic type receptors: L-AP4 and tran
s-ACPD. Both are coupled to a G protein and agonists exert their actio
n increasing phospholipase C activity which in turn induces an increme
nt of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ fro
m intracellular stores. EAA play a role in some physiological processe
s. One of them is long-term potentiation (LTP), an electrochemical phe
nomenon involved in memory consolidation. Antagonists of NMDA and AMPA
receptor prevent the development of LTP, and conversely, the agonist
of glycine site of NMDA receptor -D-cycloserine- facilitates memory co
nsolidation. Since 1957, EAA are considered neurotoxic substances and
there are many indirect evidences to support this statement. Pathogene
sis of neuronal damage elicited by EAA involves the events shown in Fi
g. 3. Prevention of the cascade of events that provokes neurotoxicity
may be achieved by NMDA antagonists, but once it has begun it may be o
nly aborted substracting the Ca2+ from the medium, using nifedipine or
blocking AMPA receptor with an antagonist (CNQX). EAA have been shown
to play a toxic role in neuronal damage induced by ischemia. Research
using various experimental models demonstrated that NMDA receptor ant
agonists (i.e. MK 801) blocks postischemic damage. Interventions at va
rious levels of the pathogenic cascade shown in Fig. 4 provoke the sam
e results. There is enough evidence to suspect that NMDA and AMPA rece
ptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) pr
event the development of epileptic seizures induced by kindling; CNQX,
an AMPA antagonist, blocks the increase in electrical activity induce
d by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blo
cks the glycine site (not strychnine sensitive) decreasing NMDA recept
or activity. Several neurodegenerative disorders have been associated
with exogenous administration or accidental intake of EAA. (i.e. neuro
latirism, Guam disease). Similarities between these diseases and later
al amiotrophic sclerosis indicate that in the latter EAA may play a pa
thogenic role. Finally, the psychotomimetic effect of phencyclidine (a
n antagonist of NMDA receptor) suggests that in schizophrenia, togethe
r with dopaminergic neurotransmission impairment, some dysfunction of
glutamate pathways may be present.