Estradiol withdrawal following a hormone simulated pregnancy induces deficits in affective behaviors and increases ∆FosB in D1 and D2 neurons in the nucleus accumbens core in mice.

In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an "estrogen withdrawal" state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.

Mechanisms for Hepatobiliary Toxicity in Rats Treated with an Antagonist of Melanin Concentrating Hormone Receptor 1 (MCHR1).

The objective of this work was to investigate the mechanisms of hepatobiliary toxicity caused by thienopyrimidone MCHR1 antagonists using BMS-773174 as a tool molecule. Co-administration of the pan CYP inhibitor 1-aminobenzotriazole with BMS-773174 prevented hepatobiliary damage, and direct delivery of the diol metabolite BMS-769750 caused hepatobiliary toxicity, identifying the diol and possibly its downstream hydroxyacid (BMS-800754) metabolite as the toxic species. Rat liver gene expression revealed treatment-related changes in hepatic transporters and induction of oval cell-specific genes including deleted malignant tumor 1 (Dmbt1). The metabolites did not alter hepatic transporter activities, suggesting that transporter-mediated cholestasis was not involved. Because injury to biliary epithelium can result in adaptive hyperplasia, rat biliary epithelial cells (BECs) were isolated and exposed to the oxidative metabolites. BMS-769750 was cytotoxic to BECs, but not rat hepatocytes, suggesting a role of the diol in biliary epithelial injury. BMS-800754 was cytotoxic to rat hepatocytes therefore its contribution to hepatocyte injury in rats is a possibility. Induction of Dmbt1 in rat BECs was investigated because of its role in hepatic progenitor cell differentiation/proliferation during injury. Dmbt1 mRNA was induced by BMS-769750, but not BMS-800754 in BECs; this induction and cellular injury was confirmed with diol metabolites formed by other compounds with the same hepatobiliary liability. In conclusion, hepatobiliary injury by thienopyrimidinone MCHR1 antagonists was driven through a CYP-mediated bioactivation pathway. Induction of Dmbt1 mRNA coupled with cellular injury suggests that injury of biliary epithelium may be the first step toward an adaptive proliferative response causing BDH by these compounds.