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Title: Subchronic administration of MK-801 in the rat decreases cortical binding of [3H]D-AP5, suggesting down-regulation of the cortical N-methyl-D-aspartate receptors.
Austin Authors: Manallack, D T;Lodge, D;Beart, P M
Affiliation: University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 16-May-1989
Publication information: Neuroscience; 30(1): 87-94
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) on N-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, goss 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 cortical N-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. The N-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 to N-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 of N-methyl-D-aspartate binding sites and suggest differential regulation of the domains of the N-methyl-D-aspartate receptor-ionophore complex.
Gov't Doc #: 2568602
Journal: Neuroscience
Type: Journal Article
Subjects: 2-Amino-5-phosphonovalerate
Ataxia.chemically induced
Cerebral Cortex.metabolism
Dizocilpine Maleate
Drug Tolerance
Nucleus Accumbens.drug effects.metabolism
Rats, Inbred Strains
Receptors, N-Methyl-D-Aspartate
Receptors, Neurotransmitter.drug effects.metabolism
Valine.analogs & derivatives.metabolism
Appears in Collections:Journal articles

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