Local cerebral glucose utilization following subacute and chronic diazepam pretreatment: differential tolerance

Abstract

Local cerebral glucose utilization (LCGU) was determined in parallel groups of conscious rats receiving diazepam (0.3 mg/kg i.v.) either acutely or following subacute (5 mg/kg i.p. daily for 3 days) or chronic (5 mg/kg i.p. daily for 28 days) diazepam pretreatment, using 2-deoxyglucose quantitative autoradiography. Acute administration of diazepam reduced LCGU in 44 of the 66 structures examined compared to vehicle-treated controls. These included limbic, cortical and extrapyramidal structures, and areas associated with sensory processing. These data are consistent with any brain regions being functionally involved in the diverse acute pharmacological effects of diazepam and with the widespread distribution of benzodiazepine receptors throughout the neuroaxis. Following subacute treatment, when animals were tolerant to the sedative effects of diazepam, glucose use remained depressed in the majority of areas studied. However, in the locus coeruleus, dorsal tegmental nucleus and most structures associated with auditory processing, tolerance to the depressant effect of diazepam upon glucose use had occurred suggesting the importance of these structures in the sedative effect of diazepam. The most striking feature of the patterns of LCGU after chronic diazepam treatment was that tolerance had occurred in the mammillary body and subiculum. However, glucose use remained depressed in hippocampal layers and in structures that provide input to the hippocampus (e.g. raphe nuclei). These data suggest that the outflow of neuronal activity from the hippocampus to the mammillary body via the subiculum is restored after chronic treatment, and may implicate these pathways in the anxiolytic action of diazepam. Overall, it would appear that different neuroanatomical substrates underlie the various pharmacological effects of diazepam and that there may be regional differences in tolerance mechanisms.