The Time-Dependent Effects of Midazolam on Regional Cerebral Glucose Metabolism in Rats

Abstract

Midazolam has hypnotic and sedative activities, which may be mediated by different neuronal structures. We investigated the time course effect of a hypnotic dose of midazolam on conscious motor behavior and on patterns of brain metabolism. Loss of nociceptive reflexes and impairment of spontaneous locomotor activity were used as indices for the hypnotic and sedative effects of midazolam, and the regional cerebral metabolic rates for glucose (rCMRglc) were used as indices of neuronal effects of midazolam. Locomotor activity was measured with a monitor and rCMRglc were measured with the quantitative autoradiographic [(14)C]2-deoxyglucose procedure in 62 brain regions of Fischer-344 rats at 2, 30, 60, 120, and 180 min after i.v. administration of saline or midazolam 5 mg/kg. After midazolam administration, rats were anesthetized at 2 min, awake but severely impaired at 30 min and slowly recovering motor activity thereafter. Anesthesia was associated with widespread rCMRglc decreases (59 areas affected, 38% mean decrease). Recovery of consciousness was associated with normalizing rCMRglc in visual, auditory, and somatosensory cortices and in the locus coeruleus (47 regions affected, 31% decrease). Recovery of motor activity was paralleled by slow rCMRglc normalization in the frontal motor, limbic, and thalamic regions (at 60, 120, and 180 min 31, 17, 4 areas affected, 26, 20, and 15% decreases from control values). Whereas the hypnotic effects of midazolam may result from inhibition of brain structures involved in arousal and sensory processing, its sedative effects may result from inhibition of subcortical motor and limbic regions.