Two thalidomide analogs induce persistent estrous behavior and inhibit uterus contractility in rats: The central role of cAMP.

The effects of 4NO2PDPMe and 4APDPMe, which are thalidomide (Tha) analogs that act as selective phosphodiesterase (PDE-4) inhibitors, on estrous behavior (lordosis and proceptive behaviors) and on uterine contraction were studied in ovariectomized (OVX) estrogen-primed Sprague Dawley (SD) and in intact non-pregnant Wistar rats, respectively. We found that intracerebroventricular (ICV) infusion of either 4NO2PDPMe or 4APDPMe (20 to 80 µg) stimulated intense lordosis and proceptive behavior in response to mounts from a sexually active male, within the first 4 h after infusion, and persisting for up to 24 h. Inhibitors of the progesterone receptor (RU486, administered subcutaneously), the estrogen receptor (tamoxifen, ICV), the adenylate cyclase (AC)/ cyclic AMP (cAMP)/protein kinase A (PKA) pathway (administered ICV), and the mitogen activated protein kinase (MAPK) pathway (administered ICV) significantly decreased lordosis and proceptive behavior induced by Tha analogs. Uterine contractility studies showed that Tha analogs inhibited both the K+- and the Ca2+-induced tonic contractions in rat uterus. Tha analogs were equally effective, but 4APDPMe was more potent than 4NO2PDPMe. These results strongly suggest the central role of cAMP in both processes, sexual behavior, and uterine relaxation, and suggest that Tha analogs may also act as Ca2+-channel blockers.

Lordosis facilitated by GPER-1 receptor activation involves GnRH-1, progestin and estrogen receptors in estrogen-primed rats.

The present study assessed the participation of membrane G-protein coupled estrogen receptor 1 (GPER-1) and gonadotropin releasing hormone 1 (GnRH-1) receptor in the display of lordosis induced by intracerebroventricular (icv) administration of G1, a GPER-1 agonist, and by unesterified 17ß-estradiol (free E2). In addition, we assessed the participation of both estrogen and progestin receptors in the lordosis behavior induced by G1 in ovariectomized (OVX), E2-benzoate (EB)-primed rats. In Experiment 1, icv injection of G1 induced lordosis behavior at 120 and 240min. In Experiment 2, icv injection of the GPER-1 antagonist G15 significantly reduced lordosis behavior induced by either G1 or free E2. In addition, Antide, a GnRH-1 receptor antagonist, significantly depressed G1 facilitation of lordosis behavior in OVX, EB-primed rats. Similarly, icv injection of Antide blocked the stimulatory effect of E2 on lordosis behavior. In Experiment 3, systemic injection of either tamoxifen or RU486 significantly reduced lordosis behavior induced by icv administration of G1 in OVX, EB-primed rats. The results suggest that GnRH release activates both estrogen and progestin receptors and that this activation is important in the chain of events leading to the display of lordosis behavior in response to activation of GPER-1 in estrogen-primed rats.