ANTIPROGESTERONE EFFECTS ON MATERNAL RECOGNITION AND BEHAVIOR IMPRINTED DURING FIRST PREGNANCY IN MICE

Anti-progesterone treatment using specific antiprogesterone antibodies or a progesterone receptor (PR) antagonist during first pregnancy impairs postpartum maternal behaviour in mice. This effect is demonstrable only if the treatment is given during pregnancy but not immediately after parturition. The purpose of the present studies was to investigate if maternal behaviour is also impaired by anti-progesterone treatment in subsequent pregnancies. Studies with a monoclonal antibody to progesterone DB3; 4.5 nmol/mouse) showed that injection of females on day 17 of second pregnancy did not cause maternal rejection but the latency of pup retrieval was prolonged especially during the first 3 days of lactation. This phenomenon was not observed in animals that had previous experience of full length lactation. Experiments were carried out with mifepristone (RU486; 10 mu g/mouse) injected at day 17 of first, second or third pregnancies. Pup rejection (22.5% vs 12.3%) and prolongation of the retrieval latency (62.3 +/- 13.3 vs 19.7 +/- 6.5 s; P < 0.02) were observed following the first pregnancy. No abnormal behavioural effects were found in mothers treated in second or third pregnancy who had prior full length lactation experience. Control females subjected to only one pup retrieval test after first delivery rejected their pups if treated in their second pregnancy (27.3% vs 4.4%; P < 0.001) and displayed a marginal prolongation of the retrieval latency period (20.9 +/- 7.0 vs 7.4 +/- 2.6 s). Antiprogesterone treatment had no negative influence when administered during third pregnancy. To determine whether treatment with RU486 (50 mu g/mouse, day 17) during first pregnancy has any residual effects, maternal response was monitored after completion of second pregnancy where no treatment was given. Females who exhibited both maternal rejection and prolonged retrieval latency following first pregnancy did not demonstrate any carryover effects during second lactation, indicating that there is no long-term consequence of RU486 treatment. These results suggest that: (i) anti-progesterone treatment of pregnant mice prevents maternal recognition and disrupts postpartum behaviour in females who had no, or very limited, nursing experience; (ii) there is a progesterone-dependent imprinting mechanism during the first pregnancy that is disrupted by anti-progesterone antibody or PR antagonist; and (iii) this imprinting mechanism and first lactation are important components of the consolidation of neural pathways that are associated with the establishment of normal maternal behaviour.