Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.
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 (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) 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(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated.
Farber
N B
NB
Department of Psychiatry, Washington University, St Louis, MO 63110, USA. farbern@psychiatry.wustl.edu
Kim
S H
SH
Dikranian
K
K
Jiang
X P
XP
Heinkel
C
C
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D002217:Carbachol / Q000008:administration & dosage / Q000633:toxicity; D002227:Carbazoles / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000648:ultrastructure; D003000:Clonidine / Q000008:administration & dosage / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007608:Kainic Acid / Q000008:administration & dosage / Q000633:toxicity; D008959:Models, Neurological; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D010620:Phenazocine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D017480:Receptors, sigma / Q000187:drug effects / Q000502:physiology; D012601:Scopolamine / Q000008:administration & dosage / Q000627:therapeutic use; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000633:toxicity
D000316:Adrenergic alpha-Agonists; D002227:Carbazoles; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011810:Quinoxalines; D017470:Receptors, Glutamate; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016291:Dizocilpine Maleate; C012134:SK&F 10047; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002217:Carbachol; C034931:rimcazole; D012601:Scopolamine; D010620:Phenazocine; D003000:Clonidine; D007608:Kainic Acid