Hoehn, Katja.2014-10-2119901990AAINN64481http://hdl.handle.net/10222/55194Excitatory amino acids (EAAs) are neurotransmitters in the neocortex; they have also been implicated in excitotoxic neuronal death during hypoxia/ischemia, hypoglycemia, and seizures. It has been suggested that the inhibitory neuromodulator, adenosine, protects against EAA-mediated neurotoxicity. (A) Both K$\sp{+}$ and glutamate released adenosine from cortical slices; NMDA, kainate and quisqualate also evoked receptor-mediated release of adenosine. K$\sp{+}$-evoked adenosine release was diminished in Ca$\sp{2+}$-free medium, while EAA agonist-evoked release was not, although kainate appeared to release adenosine from separate Ca$\sp{2+}$-dependent and independent pools. K$\sp{+}$-evoked adenosine release was partly mediated indirectly through the release of an endogenous EAA acting at NMDA receptors; ($\sp3$H) NA release was not. NMDA was 33 times more potent at releasing adenosine than ($\sp3$H) NA. NMDA-evoked ($\sp3$H) NA release was abolished by TTX, indicating that action potentials were essential; TTX only decreased adenosine release by 35%. Block of adenosine release by the uncompetitive antagonist, Mg$\sp{2+}$, was overcome by high concentrations of NMDA; block of ($\sp3$H) NA release was not overcome by high NMDA concentrations. These results suggest that maximal adenosine release requires activation of only a small fraction of available NMDA receptors (i.e. there are spare receptors for NMDA-evoked adenosine release). Released adenosine may not be neuroprotective against NMDA-mediated excitotoxicity; however, it may provide an inhibitory threshold that must be overcome before NMDA-mediated neurotransmission can proceed maximally. Adenosine may help to maintain the selectivity of NMDA-mediated processes. (B) The EAA receptors mediating adenosine release are not located on presynaptic terminals because EAA agonists did not release adenosine from cortical synaptosomes. However, L-glutamate did release adenosine but this was mediated by the Na$\sp{+}$-dependent transport of glutamate into the synaptosomes and not by EAA receptors. Unlike cortical slices, adenosine released from synaptosomes by glutamate was derived from a released nucleotide (not ATP or cyclic AMP). This non-receptor-mediated process was not observed in intact cortical slices, possibly because it is overwhelmed by receptor-mediated release. Nevertheless, this adenosine arises directly from glutamatergic nerve terminals so that it would be in an appropriate location to act at inhibitory presynaptic receptors and inhibit further release of glutamate.Thesis (Ph.D.)--Dalhousie University (Canada), 1990.Biology, Neuroscience.text