MK-801 pretreatment enhances N-methyl-D-aspartate-mediated brain injury and increases brain N-methyl-D-aspartate recognition site binding in rats.

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-immi ne 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 intraperitoneally 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 less than 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 excitatory 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 less than 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 less than 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.(ABSTRACT TRUNCATED AT 400 WORDS)