Benzodiazepine receptor sites in the human brain: autoradiographic mapping.

Receptor autoradiography was used to localize and quantify the distribution of benzodiazepine receptor sites in human post mortem materials using [3H]flunitrazepam. The distribution and density of these sites was analysed in the brains of 21 patients dying without reported neurological disease. The distribution of benzodiazepine receptors in the human brain was found to be comparable from case to case although differences in the density occurred among the brains examined. No influence of the post mortem delay, age, gender or pre mortem drug treatment on the distribution and densities was observed in our series. The highest densities of benzodiazepine receptors in human brain were localized in cortical and hippocampal areas, nucleus accumbens, amygdala and mammillary bodies. Intermediate densities were found in the basal ganglia and thalamic and hypothalamic nuclei. [3H]Flunitrazepam binding was low in the brainstem nuclei and very low in white matter. The triazolopyridazine Cl 218872, reported to differentiate between type I and type II benzodiazepine receptor sites, exhibited regional differences in affinity when used to block [3H]flunitrazepam binding. Benzodiazepine receptors in the cerebellar cortex were more sensitive to this compound than those in the dentate gyrus of the hippocampus and the tuberal nuclei of the hypothalamus. An enrichment in the concentration of type I benzodiazepine receptor Cl 218872-sensitive sites was observed in motor areas as compared to structures of the limbic system. The addition of GABA to the incubation medium resulted in an increase of [3H]flunitrazepam binding, suggesting the coupling of these sites to a GABAA receptor. The increase in binding was directly proportional to the density of benzodiazepine receptors but unrelated to the density of high-affinity GABAA sites. The distribution of benzodiazepine receptor sites in the human brain compares well with that previously described in the rat brain. The high densities of receptors localized in the limbic system and in the cortical areas suggest that the effects of benzodiazepines are mediated through an interaction with the sites we have visualized in these anatomical structures. Our results provide a detailed map of the distribution of benzodiazepine receptors and a basis for the understanding of pharmacological effects of these drugs in humans and for future studies of modifications of these receptors in neurological and neuropsychiatric conditions in humans.