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

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.