Effects of developmental cannabis exposure on prefrontocortical structure and function

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Project Summary Cannabis is the most commonly abused illicit drug in the United States. With several states recently passing legislation permitting the use of cannabis for recreational purposes, there is valid concern that this could dramatically increase the availability and use of cannabis in sensitive developmental populations. Adolescence is a period of dynamic cortical development that facilitates proper behavioral and cognitive maturation, and as such, many are worried that chronic cannabis use during this period may interfere with these important developmental processes, thereby contributing to the emergence of cognitive and/or motivational deficits in adulthood. Clinical studies have lent credence to this notion; however, the long-term causal effects of adolescent cannabis use have been difficult to elucidate. Preclinical animal models are advantageous in this respect, yet current models of cannabis exposure have been plagued by methodological concerns that limit the translatability of these data to human populations. Our laboratory has generated important new data using a novel, translationally relevant model of cannabis vapor self-administration in rats. This new method uses custom-designed equipment to deliver discrete ‘puffs’ of vaporized cannabis extracts in a response-contingent manner. This approach is unique in that it uses natural cannabis extracts (rather than synthetic cannabinoid receptor agonists or isolated cannabis constituents) that are delivered via the pulmonary route of administration that is most common in human users. We will use this innovative approach to determine the extent to which self-administration of vaporized cannabis extracts that are high in Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD) elicits long-term alterations in cortical development, cognitive flexibility, and effort-based decision making. Moreover, we will examine whether such alterations occur in an age-, sex-, and/or drug-dependent manner. For Aim 1, an automated set-shifting task will be used to assess deficits in cognitive flexibility, and an effort-discounting task will be used to assess deficits in effort- based decision-making. For Aim 2, brains will be harvested from rats tested in Aim 1 to determine whether potential treatment effects in task performance are associated with individual differences in white matter development and spine density in the prefrontal cortex (PFC). Our overarching hypothesis is that intrapulmonary self-administration of an extract high in THC will produce long-term impairments in attentional set shifting and reduce the preference for larger, more effortful rewards, especially following adolescent-onset self-administration. We further predict that these cognitive impairments will be associated with aberrations in myelination and synaptic pruning in the PFC, and that these long-term cognitive and structural impairments will be attenuated in cohorts receiving an equal ratio of the CBD-rich extract. The results are expected to positively impact the field by providing the proof-of-concept for a novel, translationally relevant model of pulmonary cannabis self-administration and delineating its long-term structural and functional consequences. Additionally, this work will provide the foundation for future studies that will dissect the mechanisms by which cannabis exposure impacts cognition, motivation, and vulnerability for addiction.