Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration

被引:172
作者
Fredriksson, A [1 ]
Archer, T
Alm, H
Gordh, T
Eriksson, P
机构
[1] Uppsala Univ, Psychiat Ulleraker, Dept Neurosci, SE-75017 Uppsala, Sweden
[2] Univ Gothenburg, Dept Psychol, S-40020 Gothenburg, Sweden
[3] Uppsala Univ, Dept Surg Sci Anaesthesiol & Intens Care, SE-75017 Uppsala, Sweden
[4] Uppsala Univ, Dept Environm Toxicol, SE-75017 Uppsala, Sweden
关键词
apoptosis; neonatal; ketamine; diazepam; fluoro-jade; motor activity; radial arm maze; swim maze; parietal cortex; Laterodorsal thalamus; NMR1; mice;
D O I
10.1016/j.bbr.2003.12.026
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
The early postnatal brain development, when many potentially sensitive processes occur, has been shown to be vulnerable to different pharmacological and environmental compounds. In the present investigation, four groups of neonatal NMRI male mice were administered the glutamate NMDA receptor antagonist ketamine (50 mg/kg, s.c.), or the GABA(A) receptor agonist diazepam (5 mg/kg, s.c.), or co-administered ketamine (50 mg/kg, s.c.) and diazepam (5 mg/kg, s.c.), or vehicle (0.9% saline, s.c.) on day 10 after birth. On day 11, mice from each treatment group were sacrificed and brains were taken for analysis of neuronal cell degeneration, using Fluoro-Jade staining technique. Ketamine, but not diazepam, induced a severe degeneration of cells in the parietal cortex. The opposite was observed for diazepam in the laterodorsal thalamus. The most pronounced cell degeneration was seen in parietal cortex of mice exposed to both ketamine and diazepam. At 2 months of age each treatment group was tested for motor activity and learning performance. Ketamine and ketamine + diazepam treated mice displayed severe deficits of habituation to the test chamber in the spontaneous motor activity test, marked deficits of acquisition learning and retention memory in the radial arm maze-learning task and less shift learning in the circular swim maze-learning task. This study indicates that the observed functional deficits can be related to cell degeneration induced during a critical stage of neonatal brain development. The potentiated apoptosis induced by ketamine and diazepam may have implications for the selection of drugs used in neonatal paediatric anaesthesia. (C) 2003 Elsevier B.V. All rights reserved.
引用
收藏
页码:367 / 376
页数:10
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