In experiment I we studied the capacity of progesterone (P) and two nonsteroidal agents that activate lordosis, but do not bind to the progestin receptor (PR), i.e. luteinizing hormone-releasing hormone (LHRH) and prostaglandin E2 (PGE2) to induce sequential inhibition (SI) in ovariectomized estradiol-primed rats. The administration of 1 mg P, 5 µg LHRH or 100 µg PGE2 induced significant lordosis within 4 h. An injection of 1 mg P, 24 h after the administration of the above lordogenic agents, induced significant lordosis in rats pretreated with LHRH or PGE2, but not in those pretreated with P. Thus, only P induced SI (p < 0.025). In experiment II we investigated if progestin-induced SI results in a reduced capacity of the subjects to respond only to P or to other lordogenic agents. The synthetic progestin norgestrel (400 µg administered 24 h earlier) significantly reduced the responsiveness to P (p < 0.01), LHRH (p < 0.01), PGE2 (p < 0.025) and dibutyryl cyclic AMP (db cAMP p < 0.01). Results suggest that SI is triggered only by agents that bind to the PR (experiment I) and that it decreases the responsiveness of rats not only to P but also to other lordogenic agents (experiment I