Chronic NMDA receptor stimulation: therapeutic implications of its effect on adenosine A1 receptors.
It is known that stimulation of adenosine A1 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 N6-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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology*; D015649:Pentostatin / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D012640:Seizures
D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1; D015649:Pentostatin; C048599:N(6)-cyclopentyladenosine; D016202:N-Methylaspartate; D000241:Adenosine