EAA receptors

The excitatoiy amino acids (EAA), glutamate and aspartate, are the principal excitatory neurotransmitters in the brain. They are released by neurons in several distinct anatomical pathways, such as corticofugal projections, but their distribution is practically ubiquitous in the central nervous system. There are both metabotropic and ionotropic EAA receptors. The metabotropic receptors bind glutamate and are labeled mGluRl to mGluRB. They are coupled via G-proteins to phosphoinositide hydrolysis, phospholipase D, and cAMP production. Ionotropic EAA receptors have been divided into three subtypes /V-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), and kainate receptors (Nakanishi 1992). 

However, it is not the only mechanism, because drugs that do not work at NMDA receptors can impair memory (e.g., benzodiazepines). Other EAA receptors include the ionotropic AMPA and kainate receptors, and the metabotropic glutamate receptors (mGluR). 

It is believed that many of the neurons in PC receive EAA inputs either from the lateral olfactory tract and/or from cortico-cortico connections within PC. Furthermore, elec-trophysiological studies show a role for EAA receptors in PC. Recent autoradiographic, in situ, and immunocytochemical evidence suggests that layer II PC contains an extensive amount of AMPA and kainate receptor subtypes, while layers la and II stain for NMD A receptors (Petralia and Wenthold, 1994 Monaghan et al. 1985 Wisden and Seeburg, 1993 Gall et al. 1990 Petralia and Wenthold, 1992, van den Pol et al. 1994 and Molnar et al. 1993). Further study of the cellular identification of these receptors within PC is necessary. 

A third excitatory amino acid (EAA) receptor that is now receiving attention is the N-methyl-D-aspartate (NMDA) receptor. This receptor may be involved in epileptic discharges and hypoxia damage. There are also selective agonists (NMDA and cyclopentane glutamate) and a selective antagonist (D-APV5) available for sophisticated studies to demonstrate the extent brain processes are affected by NMDA activation of its receptors. 

The role of EAA in cognition and learning is well established (Monaghan et al., 1989). The high level of EAA receptors in neocortical and hippocampal regions is also undoubted (Young and Egg, 1991). 

For example, pretreatment with EAA-receptor antagonists (Rothman, 1984 Simon et al., 1984) prevents the regional damage (Section 8). 

Glu is the most likely native transmitter at EAA receptors and among the proposed transmitter candidates, has the highest affinity for NMDA receptors (Olverman et al., 1984). Aspartate (Asp) is an endogenous transmitter candidate that acts with relative selectivity at NMDA sites. NMDA receptors are inhibited competitively by structural analogs of Glu that include 2-amino-5-phos-phonovalerate (APV, AP5) and 3-(( )-2-carboxypiperazin-4-yl)propyl-1 -phosphonic acid... 

Glutamate or a structurally-similar chemical is an excitatory neurotransmitter in many areas of the brain. EAA receptors are generally divided into N-methyl-D-aspartate, quisqualate and kainate receptors, named for agonists that bind to each type of receptor. Further subdivision of classes is currently underway. Stimulation of EAA receptors increases cation conductance, leading to depolarization, or stimulates phosphatidyl inositol turnover. 

Excitatory amino acids such as glutamate are thought to be important in learning, memory and other brain functions. EAA receptor deficits are present in brains of patients with Alzheimer s disease and Huntington s disease. No EAA agonists or antagonists have been approved for human use. 

EAA receptors, in balance with the receptors for the lAAs, likely are crucial for the regulation of neuronal plasticity involving dynamic changes of neurons in response to environmental stimuli. Neuronal plasticity accounts for the ability of an organism to learn and adapt, which includes both long-term potentiation and long-term depression. 

Until a few years ago, EAAs were thought to mediate their actions through three different classes of receptors [32, 33]. As the result of extensive neurochemical, pharmacological and, in recent years, molecular biological studies, central EAA receptors are now most conveniently subdivided into five main classes, some of which, if not all, are heterogeneous (Fig. 11) [34-36] ... 

Fig. 11. Schematic illustration of the multiplicity of central EAA receptors and the sites of action of a number of selective or non-selective agonists.

AMPA is a specific and very potent agonist at AMPA receptors, and radiolabelled AMPA has become the standard ligand for studies of this subtype of EAA receptors [62, 63],... 

There is substantial evidence fi om studies in the intact animal that these neurons are directly stimulated by hypoxia. Sun and colleagues have shown that microinjection of cyanide into the RVLM of rats evokes a pressor response (68). The RVLM reticulospinal sympathoexcitatory vasomotor neurons, many of which exhibit pacemaker-hke activity, are rapidly and reversibly excited in a dose-dependent manner when the cyanide is delivered by either microinjection or microiontophoresis (63,66,68,69). This excitation is not altered by blockade of ionotropic excitatory amino acid (EAA) receptors in this region (70). Fiuiher, during hypoxic excitation of these RVLM reticulospinal sympathoexcitatory vasomotor neurons, their response to baroreceptor stimulation is preserved, suggesting that the... 

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