Impacts of Prenatal Cannabis Exposure on the Medial Prefrontal Cortex in Adulthood

Darren Earl Ginder

doi:10.7273/000005131

Due to widespread legalization, cannabis has become the most commonly used drug during pregnancy. Despite this, the research surrounding the long-term impacts of prenatal cannabis exposure remain elusive, with much of the current literature reporting conflicting results. This dissertation unravels how prenatal cannabis exposure (PCE) impacts the offspring in adulthood, revealing long-term effects that alter function in the medial prefrontal cortex (mPFC). By using a novel model of cannabis vapor exposure, female rats were trained to self-administer cannabis vapor prior to, and throughout, their pregnancy. Offspring were then taken and maintained until adulthood ( > P60) and were then used to assess the impacts of PCE on the protein expression in the mPFC, projection neurons between the mPFC and nucleus accumbens (NAc), and cognitive ability. Additionally, a smaller group received the neurohormone pregnenolone during late childhood, in order to assess the effectiveness of pregnenolone as a means to restore cognitive function following PCE. Analyses of excitatory (mGLU5) and inhibitory (CB1R and PV) markers in the mPFC revealed no changes between PCE and controls, further adding to the mixed results in the literature. When examining projections from the mPFC to NAc, results revealed a sex specific impact of PCE: female PCE rats showed a higher frequency of excitatory post-synaptic currents (EPSC) compared to controls. This difference was not present in males. Additionally, a non-sex specific reduction on EPSC amplitude was seen in PCE offspring, indicating reductions in ability to generate action potentials. Finally, female offspring that experienced PCE showed higher holding current when injected with a voltage of -60mV, indicating a hyperexcitable membrane. Together, this reveals reduced communication between the mPFC and NAc and that female projection neurons were more easily excited. The last part of this dissertation aimed to restore function, as our laboratory previously showed PCE resulted in deficits in cognitive flexibility. Conducting the same cognitive assessment, this dissertation revealed that maternal self-administration of cannabis vapor resulted in offspring that could not perform an extradimensional shift when attempting to obtain a sucrose reinforcer. Furthermore, it was shown that pregnenolone is effective at restoring this ability to learn a new rule set to obtain a sucrose reinforcer. This reveals that pregnenolone protects against the cognitive impacts of PCE, at least in terms of cognitive flexibility.

Impacts of Prenatal Cannabis Exposure on the Medial Prefrontal Cortex in Adulthood

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