The Effects of the Non-Benzodiazepine Hypnotic U-85575 on the Local Cerebral Glucose Utilization of Various Rat Brain Regions Using 14C-2-Deoxyglucose
Schneider, Catherine C.
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Benzodiazepines are found to produce hypnotic effects in the rat brain by binding to a supramolecular complex, the benzodiazepine receptor (BZR). This results in a stimulation of the inhibitory neurotransmitter, GABA. Recently, a new non-benzodiazepine agent, U-85575, was discovered to produce similar EEG patterns to benzodiazepines. The purpose of the following study was to measure the local cerebral glucose utilization (LCGU) at various regions throughout rat brains treated with U-85575 alone or with the BZR antagonist, Flumazenil, in order to interpret the actions of the agent in comparison to those of benzodiazepines. LCaU can be related to metabolic rate via Sokoloffs equation (Sokoloff, 1984). Brain slicing and autoradiography were also employed to determine which areas were depressed by the drug. Results show that although U -85575 is obviously a hypnotic and a BZR agonist that affects important anxiolytic regions (limbic system) and depressant areas (cortex, hypothalamus), data reveal significant differences between the drugs. While the areas affected by U -85575 correlated closely to those depressed by the benzodiazepine, Triazolam; the actions of U-85575 were not associated specifically with either BZR subtype. In addition, key areas such as the spinal cord and hippocampus were not depressed by U -85575 but were by benzodiazepines. Flumazenil acted unexpectedly by not only antagonizing U-85575, but actually stimulating several areas on its own. Flumazenil also reversed depression by 10 mg/kg U-85575 moreso than 1 mg/kg U-85575 Based on these unexpected results, it is likely that both U -8557 5 and Flumazenil act on additional receptors besides BZR to produce their effects.