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Chronic NMDA receptor stimulation: therapeutic implications of its effect on adenosine A1 receptors
Journal article   Open access   Peer reviewed

Chronic NMDA receptor stimulation: therapeutic implications of its effect on adenosine A1 receptors

Dag K.J.E. Von Lubitz, Jeongho Kim, Mark Beenhakker, Margaret F. Carter, Rick C.-S. Lin, Yacov Meshulam, John W. Daly, Dan Shi, Li-Ming Zhou, Kenneth A. Jacobson, …
European journal of pharmacology, v 283(1-3)
05 Sep 1995
DOI: https://doi.org/10.1016/0014-2999(95)00338-L
PMID: 7498308
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc3427754View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Adenosine A1 receptor Alzheimer’s disease Mouse NMDA receptor Seizure
It is known that stimulation of adenosine A 1 receptors has a modulatory effect on the excitability of postsynaptic NMDA receptors. Conversely, acute stimulation of NMDA receptors results in release of adenosine via calcium-independent mechanisms. These findings indicate a close functional relationship between these receptors. It is, therefore, possible that chronic, low level stimulation of the NMDA receptor may have a negative impact on these modulatory processes. To investigate this possibility, we have subjected C57BL mice either to an acute injection of a N 6 -cyclopentyladenosine (CPA, 0.01 mg/kg) or deoxycoformycin (1 mg/kg) followed by a convulsant dose of N -methyl- d -aspartate (NMDA) (60 mg/kg) or to chronic, low level (20 mg/kg i.p. daily) exposure to NMDA for 8 weeks. One day after the last injection of NMDA, animals were injected either with a convulsant dose of NMDA alone, or with either CPA at 0.001 or 0.01 mg/kg, or with 1 mg/kg deoxycoformycin followed 15 min later by 60 mg/kg NMDA. Neither CPA nor deoxycoformycin were protective when NMDA was given acutely at 60 mg/kg. Chronic treatment with NMDA alone or chronic administration of NMDA followed by 0.001 mg/kg CPA had no significant effect on mortality following a convulsant dose of NMDA. However, when the chronic regimen of NMDA was followed by either 0.01 mg/kg CPA or 1 mg/kg deoxycoformycin, mortality was reduced to 10% (CPA), or eliminated completely (deoxycoformycin). Moreover, combination of chronic NMDA treatment with either CPA (both doses) or deoxycoformycin produced a significant improvement in other measures, i.e., seizure onset, intensity of neurological impairment, and extension of time to death. Consonant with these results, apparent density of adenosine A 1 receptors was increased in the cortex and hippocampus of animals treated chronically with NMDA. Our results indicate a possible role for NMDA-adenosine A 1 receptor interaction in pathologies in which chronic stimulation of the NMDA receptor by endogenous excitatory amino acids may be involved.

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Collaboration types
Domestic collaboration
Web of Science research areas
Pharmacology & Pharmacy
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