TY - JOUR
T1 - MK-801 pretreatment enhances N-methyl-d-aspartate-mediated brain injury and increases brain N-methyl-d-aspartate recognition site binding in rats
AU - McDonald, J. W.
AU - Silverstein, F. S.
AU - Johnston, M. V.
N1 - Funding Information:
Acknowledgements--Supported by USPHS grants lPOINSl9613 (M.V.J.) IKOSNSOI I7 (F.S.S.) MSTP grant S T32 6M07863-07(J .W.M.). K. Gordon MD, MS was a statisticacl onsultant.W e thank S. M. Scholler,H . M. Arft and K. T. O’Mara for technicala ssistanceM. K-801 was a gift of Dr P. Anderson, Merck. Sharp and Dohme. West Point. PA.
PY - 1990
Y1 - 1990
N2 - Direct intracerebral administration of N-methyl-d-aspartate typically produces focal brain injury. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-immine maleate (MK-801), a non-competitive N-methyl-d-aspartate antagonist, can protect against N-methyl-d-aspartate-mediated brain injury when administered shortly before or after an intracerebral injection of N-methyl-d-aspartate. However, in this study we report that in perinatal rats if MK-801 (1 mg/kg) is administered intra-peritoneally 24 h prior to a unilateral intrastriatal N-methyl-d-aspartate injection, N-methyl-d-aspartate-mediated brain injury is paradoxically enhanced. The severity of resulting brain injury is 15-25% greater in groups that received MK-801 in comparison with saline-treated controls (P < 0.001, linear regression analysis). In contrast, the severity of brain injury resulting from intrastriatal injection of the glutamate agonist quisqualate is not altered by a similar 24 h MK-801 pretreatment. Furthermore, the enhanced toxicity of N-methyl-d-aspartate produced by a 24 h pretreatment with MK-801 is completely blocked if a second dose of MK-801 is administered 15 min after the intrastriatal injection of N-methyl-d-aspartate. To determine if MK-801 produced alterations in glutamate receptor pharmacology co-incident with the enhanced toxicity of N-methyl-d-aspartate, in vitro quantitative autoradiography for excitory amino acid receptor subtypes was performed with [3H]glutamate and [3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine in seven-day-old rats killed 2 or 24 h after MK-801 (1 mg/kg) administration. A 2 h MK-801 pretreatment produced a 30-50% increase in [3H]glutamate binding at N-methyl-d-aspartate preferring recognition sites in all four brain regions examined (areas CA1 and CA3 of the hippocampus, corpus striatum, cingulate cortex) in comparison with saline-treated controls (P <0.05, ANOVA). [3H]N-1-(2-Thienyl)cyclohexyl-3,4-piperidine binding to the phencyclidine site associated with the N-methyl-d-aspartate receptor was reduced by 60-80% in all brain regions examined (P < 0.001). Quisqualate-sensitive [3H]glutamate binding was not altered by a 2 h MK-801 pretreatment. In animals that received a 24 h MK-801 pretreatment, N-methyl-d-aspartate-sensitive [3H]glutamate binding remained elevated (29% increase in CA1 and CA3, P <0.05), [3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine binding was still suppressed (40% reduction in CA1 and CA3, P < 0.05) and quisqualate-sensitive [3H]glutamate binding was reduced by 15-20% in area CA3 and in the corpus striatum (P < 0.05, ANOVA). The results suggest that MK-801 induces rapid and persistent up-regulation of N-methyl-d-aspartate receptors and sensitizes the brain to N-methyl-d-aspartate-induced injury as the level of MK-801 in the brain declines. The observations provide new information about regulation of the N-methyl-d-aspartate receptor complex and may be relevant in the analysis of the neuroprotective properties of phencyclidine receptor ligands.
AB - Direct intracerebral administration of N-methyl-d-aspartate typically produces focal brain injury. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-immine maleate (MK-801), a non-competitive N-methyl-d-aspartate antagonist, can protect against N-methyl-d-aspartate-mediated brain injury when administered shortly before or after an intracerebral injection of N-methyl-d-aspartate. However, in this study we report that in perinatal rats if MK-801 (1 mg/kg) is administered intra-peritoneally 24 h prior to a unilateral intrastriatal N-methyl-d-aspartate injection, N-methyl-d-aspartate-mediated brain injury is paradoxically enhanced. The severity of resulting brain injury is 15-25% greater in groups that received MK-801 in comparison with saline-treated controls (P < 0.001, linear regression analysis). In contrast, the severity of brain injury resulting from intrastriatal injection of the glutamate agonist quisqualate is not altered by a similar 24 h MK-801 pretreatment. Furthermore, the enhanced toxicity of N-methyl-d-aspartate produced by a 24 h pretreatment with MK-801 is completely blocked if a second dose of MK-801 is administered 15 min after the intrastriatal injection of N-methyl-d-aspartate. To determine if MK-801 produced alterations in glutamate receptor pharmacology co-incident with the enhanced toxicity of N-methyl-d-aspartate, in vitro quantitative autoradiography for excitory amino acid receptor subtypes was performed with [3H]glutamate and [3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine in seven-day-old rats killed 2 or 24 h after MK-801 (1 mg/kg) administration. A 2 h MK-801 pretreatment produced a 30-50% increase in [3H]glutamate binding at N-methyl-d-aspartate preferring recognition sites in all four brain regions examined (areas CA1 and CA3 of the hippocampus, corpus striatum, cingulate cortex) in comparison with saline-treated controls (P <0.05, ANOVA). [3H]N-1-(2-Thienyl)cyclohexyl-3,4-piperidine binding to the phencyclidine site associated with the N-methyl-d-aspartate receptor was reduced by 60-80% in all brain regions examined (P < 0.001). Quisqualate-sensitive [3H]glutamate binding was not altered by a 2 h MK-801 pretreatment. In animals that received a 24 h MK-801 pretreatment, N-methyl-d-aspartate-sensitive [3H]glutamate binding remained elevated (29% increase in CA1 and CA3, P <0.05), [3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine binding was still suppressed (40% reduction in CA1 and CA3, P < 0.05) and quisqualate-sensitive [3H]glutamate binding was reduced by 15-20% in area CA3 and in the corpus striatum (P < 0.05, ANOVA). The results suggest that MK-801 induces rapid and persistent up-regulation of N-methyl-d-aspartate receptors and sensitizes the brain to N-methyl-d-aspartate-induced injury as the level of MK-801 in the brain declines. The observations provide new information about regulation of the N-methyl-d-aspartate receptor complex and may be relevant in the analysis of the neuroprotective properties of phencyclidine receptor ligands.
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U2 - 10.1016/0306-4522(90)90377-G
DO - 10.1016/0306-4522(90)90377-G
M3 - Article
C2 - 2255390
AN - SCOPUS:0025051482
SN - 0306-4522
VL - 38
SP - 103
EP - 113
JO - Neuroscience
JF - Neuroscience
IS - 1
ER -