Reversal of the cerebral effects of diazepam in the dog by the benzodiazepine antagonist 1015–1788

In six dogs initially anesthetized with halothane-N2O-O2 for surgery and maintained during the experiment with high spinal anesthesia and local infiltration, diazepam 3.0 mg X kg-1 converted the EEG from an awake to a sleep pattern. This was accompanied by a significant 21% reduction in cerebral metabolic rate for oxygen (CMRO2) and a 15% reduction in cerebral blood flow (CBF). Substituting nitrous oxide 70% for nitrogen had no additional cerebral effects. The benzodiazepine antagonist Ro15-1788, 2 mg, completely reversed the effects of diazepam on the EEG, CMRO2 and CBF. Cerebral biopsies taken at the end of the study revealed modest but significant decreases in ATP and the energy charge along with increases in AMP, lactate and lactate/pyruvate (L/P) ratio. These changes are unexplained and suggest a possible disturbance in oxidative phosphorylation produced by Ro15-1788 preceded by diazepam.