Prenatal cannabis exposure impacts on VTA dopamine neuron physiology and adolescent stress susceptibility
Date
2024-07-03
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Abstract
Cannabis is the third most consumed drug in pregnancy, after alcohol and nicotine. As attitudes around cannabis have changed, overall use has increased, including among pregnant people. The psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC) is lipophilic and can cross the placenta to enter the fetal brain and interact with the endocannabinoid system to effect neurodevelopment. While studies have found that prenatal cannabis exposure increases opioid-seeking and alters the development of mesolimbic dopamine circuitry, its effects on other drugs and other behaviours controlled by the mesolimbic dopamine circuitry, are less understood. In chapter 2, we validate validated acute cannabis intoxication in C57Bl/6 mice with whole cannabis oil made for human consumption, using cannabis tetrad behaviours, and measuring the plasma, brain, and adipose levels of THC and its metabolites. We show that a 5 mg/kg THC dose from whole cannabis oil produces the relevant behaviours and plasma THC levels similar to human consumption of a single 15 mg dose. In chapter 3, we modeled prenatal and early postnatal cannabis exposure (PPCE) in mice, allowing dams access to 5 mg/kg THC from whole cannabis oil in peanut butter from GD1 – PD10, and measured changes in reward circuitry in the offspring. The mesolimbic dopamine circuit consists of dopamine neurons in the ventral tegmental area (VTA) which release dopamine into the nucleus accumbens (NAcc). We found PPCE affected male offspring in particular: VTA dopamine neurons were disinhibited and had increased tonic firing. However, this did not produce alterations to cocaine-seeking behaviour in a conditioned place preference task. In chapter 4, we studied how PPCE affects susceptibility to chronic mild unpredictable stress (CMUS) in adolescence. Tests of anxiety-, anhedonia-, and depression-like, as well as risky behaviours, revealed that PPCE plus CMUS increased risk-taking behaviour in a wire beam bridge task, where fasted animals must cross an unstable bridge to receive food. This thesis provides data on oral exposure to whole cannabis oil, as opposed to pure THC extract, both acutely in adults, across pregnancy, and in offspring. These results broaden our understanding of the effects of PPCE on VTA dopamine neurons, stress, and their associated behaviours.
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Keywords
cannabis, prenatal cannabis exposure, chronic stress, adolescent stress, cannabis tetrad, risk-taking, cocaine, VTA, reward, maternal-fetal transfer, oral cannabis
Citation
Peterson, C. S. (2024). Prenatal cannabis exposure impacts on VTA dopamine neuron physiology and adolescent stress susceptibility (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.