Methamphetamine exposure antagonizes N-methyl-d-aspartate receptor-mediated neurotoxicity in organotypic hippocampal slice cultures

Autor: Robert C. Holley, Katherine J. Smith, John M. Littleton, Tracy Butler, Layla Ghayoumi, Mark A. Prendergast, Michael M. Mullins, Rachel L. Self
Rok vydání: 2007
Předmět:
Male
N-Methylaspartate
Neurotoxins
Excitotoxicity
Glutamic Acid
Pharmacology
medicine.disease_cause
Binding
Competitive
Hippocampus
Receptors
N-Methyl-D-Aspartate
Synaptic Transmission
Article
Methamphetamine
Rats
Sprague-Dawley
Radioligand Assay
chemistry.chemical_compound
Organ Culture Techniques
Excitatory Amino Acid Agonists
medicine
Animals
Molecular Biology
Neurons
Dose-Response Relationship
Drug
Pyramidal Cells
General Neuroscience
Glutamate receptor
Neurotoxicity
Meth
Dextromethorphan
medicine.disease
Rats
medicine.anatomical_structure
2-Amino-5-phosphonovalerate
Animals
Newborn
nervous system
chemistry
NMDA receptor
Central Nervous System Stimulants
Female
Neurology (clinical)
Dizocilpine Maleate
Pyramidal cell
Drug Antagonism
Excitatory Amino Acid Antagonists
Developmental Biology
medicine.drug
Zdroj: Brain Research. 1157:74-80
ISSN: 0006-8993
DOI: 10.1016/j.brainres.2007.04.056
Popis: Glutamatergic systems have been increasingly recognized as mediators of methamphetamine's (METH) pharmacological effects though little is known about the means by which METH interacts with glutamate receptors. The present studies examined effects of METH (0.1-100 microM) on [3H]MK-801 binding to membranes prepared from adult rat cortex, hippocampus and cerebellum, as well as the neurotoxicity produced by 24-h exposure to N-methyl-D-aspartate (5-10 microM; NMDA) employing organotypic hippocampal slice cultures of neonatal rat. Co-incubation of [3H]MK-801 with METH (0.1-100 microM) did not reduce dextromethorphan (1 mM)-displaceable ligand binding. Exposure of slice cultures to NMDA for 24-h produced increases in uptake of the non-vital fluorescent marker propidium iodide (PI) of 150-500% above control levels, most notably, in the CA1 region pyramidal cell layer. Co-exposure to METH (1.0 microM) with NMDA (5 microM) reduced PI uptake by approximately 50% in each subregion, though the CA1 pyramidal cell layer was markedly more sensitive to the protective effects of METH exposure. In contrast, METH exposure did not reduce PI uptake stimulated by 24-h exposure to 10 microM NMDA. Co-exposure to the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (20 microM) prevented toxicity produced by exposure to 5 or 10 microM NMDA. These findings indicate that the pharmacological effects of short-term METH exposure involve inhibition of NMDA receptor-mediated neuronal signaling, not reflective of direct channel inhibition at an MK-801-sensitive site.
Databáze: OpenAIRE
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