SUMMARY1. Experiments were performed to determine whether a decrease in tissue ATP contributes to the rapid failure of cerebral synaptic transmission during hypoxia. Transmission between the perforant path and the dentate granule cells in the in vitro hippocampus was studied.2. Hippocampal slice ATP is decreased by -15% at the time that the evoked response begins to diminish in standard Krebs bicarbonate buffer. This is about 2 min after the onset of hypoxia.3. When transmission failure is accelerated by increasing extracellular K+ from 4-4 to 13-4 mM, the evoked response begins to decay about 30 see after exposure to hypoxia. There is no decrease in hippocampal slice ATP at this time. 4. However, ATP in the molecular layer (the synaptic region of the tissue) is decreased by -15 % at the time the evoked response begins to decay in the slices exposed to elevated K+ concentration. 5. Exposing the hippocampal slice to 25 mM-creatine for 3 hr elevates molecular layer phosphocreatine fourfold. Synaptic transmission during hypoxia survives three times as long as it does in the absence of creatine.6. In the creatine fortified medium, molecular layer ATP no longer declines within 30 sec of hypoxia. However the molecular layer ATP does decline within 90 sec of hypoxia, the time at which the evoked response begins to decay in this creatine-fortified buffer.7. The results establish that ATP in the region of the active synapses is lowered when the first signs of electrophysiological failure appear during hypoxia. They also show that maintaining ATP for longer than normal during hypoxia is associated with a prolonged maintenance of the evoked response. They thus suggest that a decline in ATP is one factor causing hypoxic block of synaptic transmission.8. It is further suggested that the very rapid failure of the electroencephalogram during anoxia may also result from a decline in ATP.
Synaptic transmission in cerebral tissue fails very rapidly in the absence of oxygen; the metabolic basis for this is not known. We report here that the transmission failure in the guinea pig hippocampal slice can be delayed threefold by exposing the tissue to extracellular creatine (Cr) for 3 h. The improved survival is associated with an increase of tissue phosphocreatine (PCr) concentration. These data argue that the metabolic basis for synaptic transmission failure is a fall in tissue ATP concentrations. They also indicate a way to protect brain tissue against anoxic damage.
High doses of methamphetamine (METH) produce a long-term depletion in striatal tissue dopamine content. The mechanism mediating this toxicity has been associated with increased concentrations of dopamine and glutamate and altered energy metabolism. In vivo microdialysis was used to assess and alter the metabolic environment of the brain during high doses of METH. METH significantly increased extracellular concentrations of lactate in striatum and prefrontal cortex. This increase was significantly greater in striatum and coincided with the greater vulnerability of this brain region to the toxic effects of METH. To examine the effect of supplementing energy metabolism on METH-induced dopamine content depletions, the striatum was perfused directly with decylubiquinone or nicotinamide to enhance the energetic capacity of the tissue during or after a neurotoxic dosing regimen of METH. When decylubiquinone or nicotinamide was perfused into striatum during the administration of METH, there was no significant effect on METH-induced striatal dopamine efflux, glutamate efflux, or the longterm dopamine depletions measured 7 days later. However, a delayed perfusion with decylubiquinone or nicotinamide for 6 h beginning immediately after the last METH injection attenuated the METH-induced striatal dopamine depletions measured 1 week later. These results support the hypothesis that the compromised metabolic state produced by METH administration predisposes dopamine terminals to the neurotoxic effects of glutamate, dopamine, and/or free radicals. Key Words: Methamphetamine -Dopamine-Glutamate -Striatum -Neurotoxicity-Energy metabolism.
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