Regulation of Lordosis by Cyclic 3′,5′-Guanosine Monophosphate, Progesterone, and Its 5α-Reduced Metabolites Involves Mitogen-Activated Protein Kinase

Abstract

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.

MAPK Signaling Is Critical to Estradiol Protection of CA1 Neurons in Global Ischemia

“…These findings indicate that PD98059 administered icv is neither toxic nor protective in the global ischemia model. Consistent with this, PD98059 does not impair locomotion, and its inhibitory actions on hormone-dependent behaviors are readily reversible (37,38). Together, these findings indicate that ERK/MAPK signaling is critical to estradiol protection of hippocampal neurons in a rat model of global ischemia.…”

Src kinase signaling mediates estrous behavior induced by 5β-reduced progestins, GnRH, prostaglandin E2 and vaginocervical stimulation in estrogen-primed rats

“…There is evidence that Src associated with the PR exerts its action by activating the MAPK pathway (Boonyaratanakornkit et al, 2001;Faivre et al, 2005;Migliaccio et al, 1998). Support for this mechanism comes from recent studies showing that the facilitating effect of ring A-reduced progestins, GnRH and PGE 2 was blocked by icv administration of the MAPK inhibitor PD98059 in ovx, E 2 B-primed rats (González-Flores et al, 2004b. It is unclear how the agents used in this study activate the PR-Src complex.…”

Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks

“…P 4 administration enhances cAMP in brain (Collado et al 1985) and antagonism of second messenger systems, including G-proteins, protein kinase C, or cAMP-dependent protein kinase A, in vitro, attenuates effects of 3a,5a-THP to facilitate GABA A activation (Fáncsik et al 2000). Further, the MAPK pathway has been demonstrated to be integral to progestins 0 functional effects; blocking MAPK attenuates the intracellular actions of P 4 or membrane actions of 3a,5a-THP to enhance sexual behavior among rats (González-Flores et al 2004, Acosta-Martínez et al 2006. Tomizawa et al (2003) have found that MAPK inhibition also attenuates LTP in multiparous mouse hippocampal slices.…”