COMMITTEE ON PHARMACOLOGY AND TOXICOLOGY (Graduate) In Partial Fulfillment of the Requirements For the Degree of MASTER OF SCIENCE WITH A MAJOR IN TOXICOLOGY

In this study, we investigated the effects of the peripheral benzodiazepine ligands, Ro5-4864 (putative agonist) and PK 11195 (putative antagonist) on prolactin stimulated mitogenesis in Nb2 cells. Ro5-4864 and PK 11195 at 10-9 M maximally enhanced prolactin stimulated mitogenesis. At 10-6 M Ro5-4864 inhibited prolactin stimulated mitogenesis. Clonazepam, a ligand for the central benzodiazepine receptor had no effect on mitogenesis. Interaction studies were undertaken to determine if Ro5-4864 and PK 11195 act on the same site. The ability of each ligand to enhance the mitogenic action of prolactin was blocked by a 10-6 m concentration of the other ligand. Finally, simultaneous addition of 10-9 M of the ligands resulted in no additive effect over each ligand alone. These data show that peripheral benzodiazepine ligands modulate prolactin-stimulated mitogenesis and suggests they interact at the same binding site.