MK-801 pretreatment enhances brain injury and increases brain recognition site binding in rats

Abstract

Direct intracerebral administration of typically produces focal brain injury. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-immine maleate (MK-801), a non-competitive antagonist, can protect against -mediated brain injury when administered shortly before or after an intracerebral injection of . 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 injection, -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 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 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 3H]N-1-(2-Thienyl)cyclohexyl-3,4-piperidine binding to the phencyclidine site associated with the receptor was reduced by 60-80% in all brain regions examined (P 3H]glutamate binding was not altered by a 2 h MK-801 pretreatment. In animals that received a 24 h MK-801 pretreatment, -sensitive [3H]glutamate binding remained elevated (29% increase in CA1 and CA3, P 3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine binding was still suppressed (40% reduction in CA1 and CA3, P 3H]glutamate binding was reduced by 15-20% in area CA3 and in the corpus striatum (P The results suggest that MK-801 induces rapid and persistent up-regulation of receptors and sensitizes the brain to -induced injury as the level of MK-801 in the brain declines. The observations provide new information about regulation of the receptor complex and may be relevant in the analysis of the neuroprotective properties of phencyclidine receptor ligands.