Neurodegeneration and prolonged immediate early gene expression throughout cortical areas of the rat brain following acute administration of dizocilpine

Abstract N -methyl- d -aspartate receptor antagonist drugs (NMDA-A), such as dizocilpine (MK801), induce long-lasting behavioral disturbances reminiscent to psychotic disorders in humans. To identify cortical structures affected by NMDA-A, we used a single dose of MK801 (10 mg/kg) that caused low an...

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Bibliographic Details
Published in:Neuroscience 2009-12, Vol.164 (3), p.1347-1359
Main Authors: de Olmos, S, Bender, C, de Olmos, J.S, Lorenzo, A
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cerebral Cortex - drug effects
Cerebral Cortex - metabolism
Cerebral Cortex - pathology
Dizocilpine Maleate - toxicity
Early Growth Response Protein 1 - drug effects
Early Growth Response Protein 1 - metabolism
Egr-1
Excitatory Amino Acid Antagonists - toxicity
FosB
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - drug effects
Gene Expression Regulation - physiology
Genes, Immediate-Early - drug effects
Genes, Immediate-Early - physiology
Immunohistochemistry
Male
MK-801
Nerve Degeneration - chemically induced
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
neurodegeneration
Neurology
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Parahippocampal Gyrus - drug effects
Parahippocampal Gyrus - metabolism
Parahippocampal Gyrus - pathology
Presynaptic Terminals - drug effects
Presynaptic Terminals - metabolism
Presynaptic Terminals - pathology
Proto-Oncogene Proteins c-fos - drug effects
Proto-Oncogene Proteins c-fos - metabolism
Rats
Rats, Wistar
retrosplenial cortex
somatosensory cortex
Somatosensory Cortex - drug effects
Somatosensory Cortex - metabolism
Somatosensory Cortex - pathology
Somesthesis and somesthetic pathways (proprioception, exteroception, nociception)
interoception
electrolocation. Sensory receptors
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
Time
Vertebrates: nervous system and sense organs
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Summary:Abstract N -methyl- d -aspartate receptor antagonist drugs (NMDA-A), such as dizocilpine (MK801), induce long-lasting behavioral disturbances reminiscent to psychotic disorders in humans. To identify cortical structures affected by NMDA-A, we used a single dose of MK801 (10 mg/kg) that caused low and high neurodegeneration in intact and orchiectomized male rats, respectively. Degenerating somas (neuronal death) and axonal/synaptic endings (terminal degeneration) were depicted by a silver technique, and functionally affected cortical neuronal subpopulations by Egr-1, c-Fos, and FosB/ΔFosB-immunolabeling. In intact males, MK801 triggered a c-Fos induction that remained high for more than 24 h in selected layers of the retrosplenial, somatosensory and entorhinal cortices. MK801-induced neurodegeneration reached its peak at 72 h. Degenerating somas were restricted to layer IV of the granular subdivision of the retrosplenial cortex, and were accompanied by suppression of Egr-1 immunolabeling. Terminal degeneration extended to selected layers of the retrosplenial, somatosensory and parahippocampal cortices, which are target areas of retrosplenial cortex. Induction of FosB/ΔFosB by MK801 also extended to the same cortical layers affected by terminal degeneration, likely reflecting the damage of synaptic connectivity. In orchiectomized males, the neurodegenerative and functional effects of MK801 were exacerbated. Degenerative somas in layer IV of the retrosplenial cortex significantly increased, with a parallel enhancement of terminal degeneration and FosB/ΔFosB-expression in the mentioned cortical structures, but no additional areas were affected. These observations reveal that synaptic dysfunction/degeneration in the retrosplenial, somatosensory and parahippocampal cortices might underlie the long-lasting impairments induced by NMDA-A.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2009.09.022