RELATIONSHIPS BETWEEN ATP DEPLETION, MEMBRANE-POTENTIAL, AND THE RELEASE OF NEUROTRANSMITTERS IN RAT NERVE-TERMINALS - AN IN-VITRO STUDY UNDER CONDITIONS THAT MIMIC ANOXIA, HYPOGLYCEMIA, AND ISCHEMIA

Background and Purpose It is known that the extracellular accumulation of glutamate during anoxia/ischemia is responsible for initiating neu ronal injury. However, little information is available on the release of monoamines and whether the mechanism of its release resembles that of glutamate, which may itself influence the release of monoamines by activating presynaptic receptors. This study was designed to character ize the release of both amino acids and monoamines under chemical cond itions that mimic anoxia, hypoglycemia, and ischemia. Methods The cont ents of synaptosomes in adenine nucleotides (ATP, ADP, and AMP); amino acids (aspartate, glutamate, taurine, and gamma-aminobutyric acid), a nd monoamines (dopamine, noradrenaline, and 5-hydroxytryptamine) were measured by high-performance liquid chromatography, after the synaptos omes were subjected to anoxia (KCN + oligomycin), hypoglycemia (2 mmol /L 2-deoxyglucose in glucose-free medium), and ischemia (anoxia plus h ypoglycemia). Results The anoxia- and ischemia-induced release of nora drenaline, dopamine, 5-hydroxytryptamine, and glutamate correlated wel l with ATP depletion. The correlation observed between glutamate level s and the release of dopamine and 5-hydroxytryptamine in ischemic cond itions suggests a functional linkage between the two transmitter syste ms. However, the antagonists of presynaptic glutamate receptors failed to alter the amount of monoamines released. The inhibition of Na+,K+- ATPase by ouabain had an effect similar to that produced by ischemia. Conclusions The decrease in Na+ and K+ gradients resulting from the en ergy depletion of the synaptosomes under ischemic conditions or result ing from the inhibition of Na+,K+-ATPase by ouabain promotes the rever sal of the neurotransmitter transporters. The decrease in uptake of ne urotransmitters may also contribute to the rise in the extracellular c oncentration of different transmitters observed during brain ischemia.