Subchronic administration of MK-801 in the rat decreases cortical binding of [ 3H] d-AP5, suggesting down-regulation of the corticalN-methyl- d-aspartate receptors

Abstract

The effects of the subchronic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]-cyclohepten-5,10-imine (MK-801) (0.5 mg/kg twice daily, 7 days) onN-methyl- d-aspartate, phencyclidine and sigma binding sites, behaviour and catecholamine turnover were investigated in the rat. Overt behaviours induced by MK-801 on day 7 were significantly altered relative to day 1 with subchronically treated rats not showing head weaving, gross ataxia or loss of hindlimb control: locomotion and sniffing were largely unaffected. The mean intensities of behaviour were 1.8 and 5.4 for days 7 and 1, respectively. Behavioural tolerance was accompanied by a significant reduction in the density of corticalN-methyl- d-aspartate receptors as measured by [ 3H] d-2-amino-5-phosphonopentanoic acid binding, while affinity was unchanged: the density of binding sites was 3.52 and 1.88 pmol/mg protein for saline- and MK-801-treated rats, respectively. TheN-methyl- d-aspartate ion channel as measured by the binding of[ 3H]N-(1-[2-thienyl]cyclohexyl)piperidine was not affected by the schedule of MK-801. Additionally, changes were not observed toN-methyl- d-aspartate- or glycine-stimulated[ 3H]N-(1-[2-thienyl]cyclohexyl)piperidine binding or to sigma binding. Catecholamine turnover was unaltered in the nucleus accumbens septi after the schedule of MK-801. Our results demonstrate that the subchronic administration of MK-801 produces behavioural tolerance and down-regulation ofN-methyl- d-aspartate binding sites and suggest differential regulation of the domains of theN-methyl- d-aspartate receptor-ionophore complex.