Regulation of lordosis by cyclic 3',5'-guanosine monophosphate, progesterone, and its 5alpha-reduced metabolites involves mitogen-activated protein kinase.

Progesterone (P) and its ring A-reduced metabolites regulate sexual behavior in ovariectomized, estrogen-primed female rats when they are administered intracerebrally and systemically. The present study tested the hypothesis that the MAPK pathway participates in P facilitation and sequential inhibition of sexual behavior. The role of MAPK in lordosis facilitation by two ring A-reduced metabolites of P, 5alpha-dihydroprogesterone (5alpha-DHP) and 5alpha,3alpha-pregnanolone (5alpha,3alpha-Pgl), was also assessed. In Experiment 1, the MAPK inhibitor PD98059 was infused intracerebroventricularly before progestin administration. Lordosis behavior induced by P, 5alpha-DHP, and 5alpha,3alpha-Pgl was abolished 2 h after progestin administration by PD98059. P and 5alpha,3alpha-Pgl facilitation of proceptive behaviors was also decreased by the MAPK inhibitor. Experiment 2 examined the effects of MAPK inhibition on P sequential inhibition. Estrogen-primed females received intracerebroventricular infusions of PD98059 or vehicle 30 min before systemic administration of P and were tested for lordosis 4 h later. Animals received a second injection of P 24 h later and were retested for lordosis. The MAPK inhibitor blocked both lordosis facilitation and sequential inhibition produced by systemic administration of P. Because cGMP can also facilitate lordosis behavior, and cGMP-dependent protein kinase can activate MAPK, experiment 3 determined whether interference with MAPK would affect cGMP enhancement of lordosis. The icv infusion of PD98059 significantly inhibited lordosis behavior induced by 8-bromo-cGMP, a cell-permeable cGMP analog, at both 2 and 4 h. These data support the hypothesis that the MAPK pathway is involved in lordosis regulation by P and some of its ring A-reduced metabolites as well as by the second messenger, cGMP.