Release of endogenous adenosine and its metabolites by the activation of NMDA receptors in the rat hippocampus in vivo.

1. The effects of N-methyl-D-aspartate (NMDA), KCl, and veratridine on the release of endogenous adenosine and its metabolites, inosine and hypoxanthine, from the rat hippocampus have been studied by in vivo microdialysis. 2. In the hippocampus of rats anaesthetized with urethane the adenosine level reached a stable state estimated at 0.93 microM during the first 2 h after the implantation of the dialysis probe. NMDA (50 microM to 25 mM) in the perfusate evoked a concentration-dependent release of adenosine, inosine and hypoxanthine with an EC50 of 180 microM. The release was reduced by 93% by the specific NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (2-AP5) at 200 microM, indicating an NMDA receptor-mediated process. In addition, the 100 mM KCl-evoked release of adenosine was also substantially reduced by 77% by 2-AP5, suggesting that a large component of the K(+)-evoked release is NMDA-receptor-mediated. 3. Perfusion with zero-Ca2+ artificial cerebrospinal fluid attenuated the NMDA-evoked release of adenosine only by 16% (not significant) but depressed the K(+)-evoked release by 62%, indicating that most of the NMDA-evoked release is directly receptor-mediated, whereas a large component of the K(+)-evoked release could be via the release of an excitatory amino acid acting at the NMDA receptors.