MODULATION OF [H-3] FLUNITRAZEPAM BINDING BY NATURAL AND SYNTHETIC PROGESTATIONAL AGENTS

Progesterone is metabolized by ring-A reduction with subsequent oxidor eduction to 3alpha-hydroxy-5alpha-dihydroprogesterone (3alpha-OH-5alph a-DHP), a naturally occurring metabolite that has been shown to enhanc e [H-3]flunitrazepam ([H-3]FNZ) binding. Medroxyprogesterone acetate ( MPA), a commonly prescribed progestational agent, is a synthetic proge sterone derivative that has a metabolic profile similar to that of pro gesterone. In this study, the effects of MPA and its ring-A reduced me tabolites DHMPA and THMPA on [H-3]FNZ binding were investigated. While known modulators of specific [H-3]FNZ binding demonstrated expected e ffects in frozen and fresh rat cortical tissue, 3alpha-OH-5alpha-DHP e nhanced [H-3]FNZ binding only in fresh, not frozen, tissue. Neither DH MPA nor THMPA affected binding, while MPA partially inhibited [H-3]FNZ binding by 40%. In addition, five test drugs were used to assess the effect of gender and hormonal status on [H-3]FNZ binding. Neither gend er nor hormonal status influenced binding. Thus, ring-A reduced metabo lites of progesterone but not of MPA enhance [H-3]FNZ binding. The cli nical implications of these in vitro results are currently under inves tigation.