PUTATIVE BENZODIAZEPINE PARTIAL AGONISTS DEMONSTRATE RECEPTOR HETEROGENEITY

This study explored whether the behavioral heterogeneity of benzodiaze pine receptor (BDZR) ligands is a consequence of multiple receptor sub types or partial agonism. Putative partial agonists Ro16-6028, Ro23-15 90, Ro23-0364, and abecarnil were compared with U78875, a mixed agonis t-antagonist, and CGS8216, an inverse agonist, in five BDZR-mediated f unctions: hyperphagia, anxiolysis, sedation, hypothermia, and anticonv ulsant activity. Only abecarnil was an agonist in all end points. Each of the other drugs exhibited qualitatively different responses at the se end points. specifically, Ro23-0364 produced no effect on body temp erature, but was an agonist at other tests. Ro23-1590 had no effect on anxiolysis and hypothermia, but was an agonist at other tests. In con trast to other putative partial agonists, Ro16-6028 was found to be an antagonist in sedation and U78875 was an antagonist in hypothermia, b ut both were agonists at other end points. These qualitative differenc es in activity in the five behavioral end points studied cannot be exp lained by partial agonism at a single receptor and indicate that these ligands differentially activate multiple BDZR subtypes.