Flumazenil induces localised increases in glucose utilization during diazepam withdrawal in rats

The quantitative [14C]2-deoxyglucose autoradiographic technique has been employed to identify the neural circuits involved in diazepam withdrawal. Local cerebral glucose utilization (LCGU) was assessed in parallel groups of rats chronically treated with diazepam (5 mg/kg i.p., daily for 28 days), in rats that were withdrawn from chronic diazepam 24 h previously and in those that received flumazenil (5 mg/kg i.v.) immediately or 24 h after the last dose of diazepam. Two further groups received chronic vehicle or acute flumazenil (5 mg/kg i.v.). Rats withdrawn from diazepam 24 h previously did not produce changes in LCGU in the 51 structures examined compared with both control and chronic diazepam treated groups, suggesting that spontaneous withdrawal from small doses of diazepam does not evoke marked alterations in functional activity. In contrast, flumazenil-precipitated diazepam withdrawal produced a marked increase in glucose use in structures of the Papez circuit of emotion (mammillary body, anterior thalamus, cingulate cortex), together with increases in the septal nucleus, basolateral amygdala and nucleus accumbens. Less widespread increases in glucose use occurred in primary auditory and visual areas and in extrapyramidal areas. This pattern resembles that produced after acute FG-7142 administration (Brain Res., 475 (1988) 218-231). In rats receiving flumazenil 24 h after the last dose of diazepam there was a similar, but more restricted, pattern of change in LCGU. Flumazenil had no effect on LCGU in drug naive rats. Thus, flumazenil could only exert an effect upon LCGU in rats chronically treated with diazepam. These data provide functional neuroanatomical evidence for a withdrawal shift in the inverse agonist direction after chronic diazepam and suggest that flumazenil-precipitated withdrawal changes may merely be a reflection of this phenomenon.