CARBON MONOXIDE AND PREGNANCY: A SEARCH FOR A POSSIBLE THERAPEUTIC IN THE TREATMENT OF PRE-ECLAMPSIA

Pre-eclampsia (PE) is a pregnancy disorder that affects roughly 5-7% of all pregnancies and is a leading cause of both maternal and fetal/neonatal morbidity and mortality. With no present cure for the disease, researchers are interested in the lower incidence of PE observed among the cigarette smoking pregnant population. However, women who use smokeless tobacco do not experience the same decreased incidence of PE, leading to hypothesis of protection against PE from the largest combustible product of cigarette smoke, carbon monoxide (CO). Studies evaluated levels of CO in PE women and found that they were statistically lower than those of healthy pregnancy. Researchers have found CO to possess many cytoprotective and regulatory properties and specifically within the placenta, it has been found to increase perfusion pressure, decrease oxidative stress, decreases ischemia/reperfusion induced apoptosis and maintain endothelial functioning. The idea for use of CO as a possible therapeutic for PE has thus become a real possibility. This study determined CO levels in pregnant women ± smoking as well as in PE women±smoking, as to discover a possible therapeutic range for future treatments. The best correlated automated CO measurement device with blood CO levels was determined, for use in future clinical studies. This thesis also sought a possible CO delivery concentration, in order to achieve the CO levels observed in the human correlation study. A threshold level of maternal CO exposure in a murine animal model was found, for which fetal and maternal negative toxicities were not observed. The results of this thesis lend a few more pieces to the complicated puzzle involving CO and PE and offer another step toward the possibility of a therapeutic treatment/prevention using this gaseous molecule.

Impaired GABA Plasticity at ovBNST Synapses Predicts Compulsive Drinking in Schedule-Induced Polydipsia

Schedule-Induced Polydipsia (SIP) is an animal model of adjunctive drinking induced when a hungry rat receives food on a fixed interval of time. This model has been implemented as a model of compulsive behaviour and may represent a powerful tool to understand the neural mechanisms of compulsion. The bed nucleus of the stria terminalis (BNST) is thought to translate challenges to energy homeostasis into consummatory behaviours, and is therefore likely to contribute to drinking behaviours displayed by food restricted rats in the SIP paradigm. Furthermore, the BNST seems implicated in various compulsive behaviors, including compulsive water drinking in rats. Therefore, the goal of this project was to determine whether compulsive drinking in the SIP paradigm was associated with alterations in transmission at oval BNST (ovBNST) synapses. Rats undergoing the SIP procedure had restricted food access (1-hours/day) for a total of 29 days. After 7 days of food restriction and for the next 21 consecutive days, the rats had daily 2-hour access to operant conditioning chambers where they were presented with a 45-mg food pellet every minute. Water consumed during these 2-hour sessions was measured and the rats that drank 15 ml or more water for a minimum of 3 consecutive days were considered High Drinkers (HD; n=17) or otherwise, Low Drinkers (LD; n=13). Brain slices whole-cell patch clamp recordings conducted 18-hours after the last SIP training showed that chronic food restriction changed low frequency stimulation (LFS) - induced long-term potentiation of ovBNST inhibitory synaptic transmission (iLTP) into LFS - induced long-term depression (iLTD) in a majority of neurons, regardless of drinking behaviours. However, ad libitum access to food between the last day of SIP training and brain slice recordings (18-hour refeed) rescued LFS-induced iLTP in LD but not in HD, suggesting that impaired bi-directional plasticity of ovBNST synapses may contribute to compulsive drinking in the SIP paradigm.