Brain NMDA receptor

At present, the only brain manipulation that produces a clinical state behaviorally indistinguishable from schizophrenia is the blockade of brain NMDA receptors. The primary concept underlying glutamatergic models of schizophrenia, therefore, is that the dysfunction or dysregulation of NMDA receptor-mediated neurotransmission represents the common final mechanism underlying the symptom formation in schizophrenia. Although in some individuals, the NMDA dysfunction may be related to disturbances of the receptors themselves, for other individuals, these deficits may relate more to impairments of either upstream or downstream elements involving pre- and postsynaptic neural elements respectively. 

NMDA receptors bind glutamate, the major excitatory neurotransmitter in the brain. NMDA receptors regulate how excited or stimulated the nervous system is and they are also involved with learning and memory processes. Silvia L. Cruz,... 

In addition to halopeiidol, the putative neuroleptics, limcazole (311), lemoxipiide (312), and gevotioline (313) bind to (7-ieceptois as does the dopamine uptake blocker, GBR 12909 (314) and two ligands active at the NMDA receptor, ifenprodil (315) and CNS 1102 (316). NPC 16377, (317) is a selective (7-teceptor ligand. MAO inhibitors and antidepressants also bind to (7-teceptors. Some evidence indicates that (7-teceptors in the brain are in fact a form of cytochrome which may account for the diversity of ligands interacting with (7-sites. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Calton JL, Wilson WA, Moore SD Reduction ofvoltage-dependent currents by ethanol contributes to inhibition of NMDA receptor-mediated excitatory synaptic transmission. Brain Res 816 142—148, 1999... 

Monyer H, Bumashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12(3) 529-540... 

Toggas SM, Masliah E, Mucke L (1996) Prevention of HIV-1 gpl20-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res 706 303-307... 

Figure 3.1 Schematic representation of a generic excitatory synapse in the brain. The presynaptic terminal releases the transmitter glutamate by fusion of transmitter vesicles with the nerve terminal membrane. Glutamate diffuses rapidly across the synaptic cleft to bind to and activate AMPA and NMDA receptors. In addition, glutamate may bind to metabotropic G-protein-coupled glutamate receptors located perisynaptically to cause initiation of intracellular signalling via the G-protein, Gq, to activate the enzyme phospholipase and hence produce inositol triphosphate (IP3) which can release Ca from intracellular calcium stores...

While there are some reports of increased NMDA and non-NMDA receptor number in various cortical regions of schizophrenics including the prefrontal cortex, there are also indications of impaired glutamate innervation, such as reduction in its neuronal uptake sites (Ishimaru, Kurumaji and Torn 1994). Also it has been found that levels of the mRNA for the NRI subunit of the NMDA receptor in the hippocampus and its D-aspartate binding sites in the temporal cortex are both reduced more on the left than right side in schizophrenic brain. This is another indication of greater malfunction on the left side of the brain and the possibility that some schizophrenic symptoms arise from an imbalance between cross-cortical activity. 

NMDA receptor Post-mortem brain i Affinity of glutamate site... 

Status epilepticus occurs because the brain fails to stop an isolated seizure. The exact reason for this failure is unknown and probably involves many mechanisms. A seizure is likely to occur due to a mismatch of excitatory and inhibitory neurotransmitters in the brain. The primary excitatory neurotransmitter in the brain is glutamate. Glutamate stimulates postsynaptic N-methyl-D-aspartate (NMDA) receptors in the brain, causing an influx of calcium into the cells and depolarization of the neuron. Sustained depolarization may maintain SE and eventually cause neuronal injury and death.7 The primary... 

The AMPA receptors mediate the majority of fast excitatory neurotransmission in the mammalian brain. The rapid kinetics and the low Ca permeability make these receptors ideal for fast neurotransmission without sufficient changes in the intracellular calcium concentration to activate Ca2+-dependent processes. The NMDA receptors are co-localized with the AMPA receptors on many synapses, but the slow kinetics of the NMDA receptor minimize the receptor activation after a single presynaptic glutamate release where the neuron quickly repolarizes, resulting in Mg2+ block... 

---