| dc.description | Excitatory amino acids (EAAs) such as glutamate and aspartate are the major excitatory neutransmitters in the cerebral cortex. EEAs, acting at both NMDA and non-NMDA receptors, release the inhibitory neuromodulator adenosine from superfused cortical slices. Results with Mg$\sp{2+}$, MK-801 and 7-chlorokynurenic acid, which are non-competitive NMDA antagonists, indicate that there may be spare receptors for NMDA-evoked adenosine release, possibly contributing to the previously observed 33-fold increased potency of NMDA at releasing adenosine vs. ($\sp3$H) noradrenaline. Endogenous glycine, acting at a strychnine-insensitive glycine binding site on the NMDA receptor, is required for NMDA receptor mediated release of adenosine and ($\sp3$H) noradrenaline. However, heterogeneous glycine concentrations within the cortical slices cannot account for the observed spare receptor phenomenon for NMDA-evoked adenosine release. Pretreatment of slices with a concentration of NMDA (10 $\mu$M) which releases substantial adenosine but very little ($\sp3$H) noradrenaline decreased subsequent 100 $\mu$M NMDA-evoked ($\sp3$H) noradrenaline release. 8-Phenyltheophylline partially reversed this inhibition but had no effect on ($\sp3$H) noradrenaline release evoked by 100 $\mu$M NMDA alone. This indicates that adenosine, released during submaximal NMDA receptor activation, may provide a purinergic inhibitory threshold which must be overcome in order for other NMDA-mediated processes to proceed maximally. Studies characterizing the nature of the purines released during EAA receptor stimulation indicate that activation of non-NMDA receptors releases adenosine per se in a Ca$\sp{2+}$-independent manner. In contrast, NMDA receptor activation releases a nucleotide which is subsequently converted extracellulary to adenosine; in this case, release is Ca$\sp{2+}$-dependent. Although neither NMDA- nor non-NMDA-evoked adenosine release occurs via the DPR-nucleoside transporter, this transporter does appear to be a major route for removal of this adenosine from the extracellular space. IBMX, a non-selective phosphodiesterase inhibitor, blocked NMDA- but not kainate- nor AMPA-evoked adenosine release. This inhibition was not accompanied by enhanced cAMP recovery, probenecid did not block the nucleotide release and forskolin slightly increased NMDA-evoked release. These findings suggest that cAMP may be degraded intracellularly to 5$\sp\prime$AMP which is then released and converted to adenosine by ecto-5$\sp\prime$-nucleotidase. Results with more selective PDE inhibitors indicate that IBMX may exert its effects independent of PDE inhibition. NMDA-evoked adenosine release is not mediated by NO production, calmodulin, arachidonic acid release or intracellular Ca$\sp{2+}$ release, all of which have been shown to be required for NMDA-dependent long-term potentiation in the hippocampus. | en_US |
