Increased expression of neuronal Src and tyrosine phosphorylation of NMDA receptors in rat brain after systemic treatment with MK-801

We have observed that systemic treatment with the uncompetitive N-methyl-D- aspartate (NMDA) receptor antagonist MK-801 increases Src expression and NM DA receptor phosphorylation in rat brain. A partial cDNA encoding rat neuro nal Src was isolated and its sequence was used to design specific oligonucl eotide probes. Systemically administered MK-801 (5 mg/kg for 4 h) increased by 28+/-4% mRNA expression of neuronal Src in the superficial layers of th e parietal cortex. This effect was observed at doses as low as 0.2 mg/kg. A similar, although more modest, induction was observed 6 h after phencyclid ine (15 mg/kg) administration, but not after high doses of memantine and ke tamine. The MK-801-induced effect was not blocked by pretreatment with cloz apine. Consistent with the increase in mRNA levels, cortical Src protein wa s increased to 186 +/- 24% of control 24 h after MK-801 treatment. Total ce llular Src activity was also increased in parietal cortex homogenates 4 h a fter MK-801 (5 mg/kg). Moreover, MK-SOI treatment (0.5 mg/kg and 5 mg/kg fo r 4 h) increased tyrosine phosphorylation, but not protein levels, of the N MDA receptor subunit NR2A. These results provide evidence for a contributio n of Src and tyrosine phosphorylation of NMDA receptors in the pharmacologi cal actions of uncompetitive NMDA receptor antagonists. (C) 2001 Elsevier S cience Ltd. All rights reserved.