Development NMDA receptors

Antagonists such as D-(-)-2-amino-5-phosphono-valeric acid (D-AP V), which competitively block NMDA receptors, cause numerous side-effects such as memory impairment, psychotomimetic effects, ataxia and motor dis-coordi-nation, since they also impair normal synaptic transmission. The challenge has therefore been to develop NMDA receptor antagonists that prevent the pathological activation of NMDA receptors but allow their physiological activation. 

From this survey it is clear that just as normal neuronal function requires appropriately balanced inhibitory and excitatory controls so the generation of interictal spikes depends on disturbances in both. Clearly activity cannot spread without the activation of excitatory circuits, in which NMDA receptors play an important role, but it will be much facilitated by reduced inhibition (Masukawa et al. 1989). These observations may help to explain the establishment of a focus and the development of the interictal spike, but why activity can only spread to seizure proportions, at certain times, is less clear. It will, however, again require overactivity of excitatory circuits inadequately controlled by inhibitory processes. Since these controls are mediated by... 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

Guilarte TR, Miceli RC, Jett DA. 1995. Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex effects of neuronal development. Neurotoxicology 16 63-71. 

Schenk S., Valadez A., McNamara C. et al. Development and expression of sensitization to cocaine s reinforcing properties role of NMDA receptors. Psychopharmacology. 111 332, 1993. 

A few infants have been treated with antagonists of the NMDA receptor, an excitatory glutamatergic receptor for which glycine is a co-agonist (see Ch. 15) [29], Ketamine and dextromethorphan have been used with inconclusive results. Some infants may have had an improvement of their irritability and electroencephalogram. One infant, treated with both benzoate and dextromethorphan, was seizure-free by 12 months of age and had only moderately delayed development. However, this favorable experience has not always been duplicated. Treatment with dextromethorphan at the recommended dosage (maximum 5mg/kg/day) seems to be well-tolerated. 

Krystal, J. H., D Souza, D. C., Mathalon, D. et al. NMDA receptor antagonist effects, cortical glutamatergic function and schizophrenia toward a paradigm shift in medication development. Psychopharmacology 169 215-233, 2003. 

Elliott K, Kest B, Man A, Kao B, Inturrisi CE. (1995). N-methyl-D-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development. Neuropsychopharmacology. 13(4) 347-56. 

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