Browsing by Author "Borgland, Stephanie L."

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    Development and Validation of an Animal Model of Gestational Cannabis Exposure: Prenatal and Postnatal Outcomes
    (2024-09-13) Baglot, Samantha Lorraine; Hill, Matthew N.; Kurrasch, Deborah M.; Borgland, Stephanie L.
    Cannabis is one of the most widely used drugs, even during pregnancy. Clinical and preclinical research have shown important but variable effects of prenatal cannabis exposure (PCE) on cognitive, social, emotional, and metabolic domains. Preclinical studies allow for precise control and mechanistic exploration; however, studies utilizing translational routes of administration (such as inhalation) are limited. The overall aim of this thesis was to validate a preclinical model of cannabis inhalation and then use that model during pregnancy to examine maternal-fetal transmission and both pre- and post-natal outcomes across several domains. In chapter 2, we characterized and validated a preclinical model of cannabis inhalation and compared pharmacokinetics with injection exposure. Despite comparable dosages and similar peak blood THC levels following inhalation and injection, we found drastically different metabolism and pharmacokinetics of THC and metabolites. In chapter 3, we validated a preclinical model of inhaled PCE and compared maternal-fetal transmission to a common PCE injection model. We found that inhalation exposure resulted in a transmission rate (from maternal blood to fetal brain) of about 30%, whereas injection resulted in roughly 100%. These studies were the first to directly compare THC and metabolite levels following inhalation or injection in adulthood and during pregnancy, and taken together our results suggest that animal models need to consider route of administration when discussing translational implications. In chapter 4 and 5, we aimed to examine the effects of inhaled PCE on several pre- and postnatal outcome domains. In general, we found that PCE resulted in altered early-life immune profile, reduced social investigation, elevated stress-response in adult males, altered glucose metabolism that was sex and diet dependent, modified food choice, and reduced sucrose preference in adulthood. However, we also found that PCE did not alter maternal outcomes, litter size or birthweight, embryonic endocannabinoid or stress system functioning, adolescent structural brain development or social play behaviour, and adult anxiety-like behaviour, bodyweight, or adiposity. Collectively, these studies provide a large overview of the effects of PCE utilizing a moderate inhalation dosage and may help promote more accurate public health messaging around the risk of cannabis use during pregnancy.
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    GABA(B) modulation of dopamine release in the nucleus accumbens core
    (Wiley, 2014-11) Puil, Ernest; Pitman, Kimberley A.; Borgland, Stephanie L.
    Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ-Aminobutyric acid type B (GABAB ) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABAB receptors, can decrease drug-seeking behaviours. However, the mechanism by which GABAB receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast-scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration-dependently decreased single pulse-evoked DA release. This effect was blocked by the GABAB antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D2 receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D2 receptors. Baclofen-mediated suppression of DA release persisted after a locomotor-sensitizing cocaine treatment, indicating that GABAB receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen-mediated suppression of terminal DA release is due to GABAB activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment.