CHRONIC NMDA RECEPTOR STIMULATION - THERAPEUTIC IMPLICATIONS OF ITS EFFECT ON ADENOSINE A(1) RECEPTORS

It is known that stimulation of adenosine A(1) receptors has a modulat ory effect on the excitability of postsynaptic NMDA receptors. Convers ely, acute stimulation of NMDA receptors results in release of adenosi ne via calcium-independent mechanisms. These findings indicate a close functional relationship between these receptors. It is, therefore, po ssible that chronic, low level stimulation of the NMDA receptor may ha ve a negative impact on these modulatory processes. To investigate thi s possibility, we have subjected C57BL mice either to an acute injecti on 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 w ere injected either with a convulsant dose of NMDA alone, or with eith er CPA at 0.001 or 0.01 mg/kg, or with 1 mg/kg deoxycoformycin followe d 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 b y either 0.01 mg/kg CPA or 1 mg/kg deoxycoformycin, mortality was redu ced to 10% (CPA), or eliminated completely (deoxycoformycin). Moreover , combination of chronic NMDA treatment with either CPA (both doses) o r deoxycoformycin produced a significant improvement in other measures , i.e., seizure onset, intensity of neurological impairment, and exten sion of time to death. Consonant with these results, apparent density of adenosine A(1) receptors was increased in the cortex and hippocampu s of animals treated chronically with NMDA. Our results indicate a pos sible role for NMDA-adenosine A(1) receptor interaction in pathologies in which chronic stimulation of the NMDA receptor by endogenous excit atory amino acids may be involved.