BINDING PROFILES AND PHYSICAL-DEPENDENCE LIABILITIES OF SELECTED BENZODIAZEPINE RECEPTOR LIGANDS

In vitro binding profiles were determined for selected benzodiazepine receptor (BZR) ligands by quantitative radioautography in rat brain. T he ligands represent subtype-selective agonists (zolpidem) or nonselec tive BZR agonists (diazepam), as well as BZR partial agonists (bretaze nil, Ro 43-9624, and Ro 19-8022), In addition, these compounds were ev aluated in a precipitated withdrawal paradigm in monkeys, The physical dependence liability was not clearly related to the in vitro brain BZ R binding profiles of these compounds. Therefore, diazepam, bretazenil , Ro 19-8022, and Ro 43-9624 had regional affinities for the 13 select ed rat brain regions that were close to the mean values across regions , despite the clearly greater physical dependence potential of diazepa m, Zolpidem, on the other hand, had regional affinities for the 13 rat brain regions that diverged significantly from the mean value across regions and exhibited a lower physical dependence potential than diaze pam. These results raise the possibility that a combination of BZR sub type selectivity with partial agonism could yield a marked reduction o f physical dependence liability. (C) 1998 Elsevier Science Inc.