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 imp airs postpartum maternal behaviour in mice. This effect is demonstrabl e only if the treatment is given during pregnancy but not immediately after parturition. The purpose of the present studies was to investiga te if maternal behaviour is also impaired by anti-progesterone treatme nt in subsequent pregnancies. Studies with a monoclonal antibody to pr ogesterone DB3; 4.5 nmol/mouse) showed that injection of females on da y 17 of second pregnancy did not cause maternal rejection but the late ncy of pup retrieval was prolonged especially during the first 3 days of lactation. This phenomenon was not observed in animals that had pre vious experience of full length lactation. Experiments were carried ou t 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 prol ongation 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 behav ioural effects were found in mothers treated in second or third pregna ncy who had prior full length lactation experience. Control females su bjected to only one pup retrieval test after first delivery rejected t heir pups if treated in their second pregnancy (27.3% vs 4.4%; P < 0.0 01) and displayed a marginal prolongation of the retrieval latency per iod (20.9 +/- 7.0 vs 7.4 +/- 2.6 s). Antiprogesterone treatment had no negative influence when administered during third pregnancy. To deter mine whether treatment with RU486 (50 mu g/mouse, day 17) during first pregnancy has any residual effects, maternal response was monitored a fter completion of second pregnancy where no treatment was given. Fema les who exhibited both maternal rejection and prolonged retrieval late ncy following first pregnancy did not demonstrate any carryover effect s during second lactation, indicating that there is no long-term conse quence of RU486 treatment. These results suggest that: (i) anti-proges terone treatment of pregnant mice prevents maternal recognition and di srupts postpartum behaviour in females who had no, or very limited, nu rsing experience; (ii) there is a progesterone-dependent imprinting me chanism during the first pregnancy that is disrupted by anti-progester one antibody or PR antagonist; and (iii) this imprinting mechanism and first lactation are important components of the consolidation of neur al pathways that are associated with the establishment of normal mater nal behaviour.