The time-dependent effects of midazolam on regional cerebral glucose metabolism in rats.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Freo
Ulderico
U
Institute of Anesthesiology and Intensive Care, Department of Pharmacology and Anesthesiology, University of Padova, Via C. Battisti 267, 35121 Padova, Italy. ulderico.freo@unipd.it
Dam
Mauro
M
Ori
Carlo
C
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003243:Consciousness / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012018:Reflex / Q000187:drug effects; D013997:Time Factors
D006993:Hypnotics and Sedatives; D005947:Glucose; D008874:Midazolam