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Cited 107 time in webofscience Cited 115 time in scopus
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Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity

Authors
Farber, NBKim, SHDikranian, KJiang, XPHeinkel, C
Issue Date
2002
Publisher
NATURE PUBLISHING GROUP
Keywords
neurodegeneration; retrosplenial cortex; MK801; dissociative anesthetics; Alzheimer's disease; schizophrenia; psychosis; rodents; rats
Citation
MOLECULAR PSYCHIATRY, v.7, no.1, pp 32 - 43
Pages
12
Indexed
SCIE
SCOPUS
Journal Title
MOLECULAR PSYCHIATRY
Volume
7
Number
1
Start Page
32
End Page
43
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/22201
DOI
10.1038/sj/mp/4000912
ISSN
1359-4184
1476-5578
Abstract
NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (eg antimuscarinics, non-NMDA glutamate antagonists, and a, adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m.) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotornimetic effects of NRHypo are mediated.
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