Sex differences in THC/CBD self-administration of vulnerable age groups throughout the life span

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Legalization and shifting societal views have contributed to increases in the use of recreational and medicinal cannabis products in the general population, especially among vulnerable populations. Despite this increase, there are significant gaps in our understanding of how sex and age contribute to Cannabis Use Disorder (CUD) and the cognitive impacts of chronic cannabis exposure. Our goal in this preclinical component is to enhance and inform Clinical Projects 1-3 by investigating numerous biological endpoints after Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) vapor self-administration in rats. Our project will assess these outcomes using translationally relevant behavioral and biological assessments in several vulnerable groups that correspond to the Clinical Projects: emerging young adults (Project 1), aged adults (Project 3), and pregnant females (Project 2). Our central hypothesis is that both sex and age confer unique neurobiological vulnerabilities to volitional THC/CBD administration, resulting in different behavioral and molecular outcomes. To test this, we will assess sex and age differences in THC/CBD intake, reinstatement to THC/CBD-associated cues, stress reactivity, cognitive function, and the molecular footprint of THC/CBD in the brain across the 3 Aims. In all 3 Aims, we will employ an ecologically valid model of rodent cannabis vapor self-administration (SA) to assess volitional THC/CBD intake. In Aim 1, we will assess volitional THC vapor SA in adolescent male and female rats. We expect that female rats will take more THC/CBD and relapse to a greater extent than males. In behavioral assessments, we predict that females will exhibit enhanced stress reactivity, while males will have deficits in spatial memory. In Aim 2, we will conduct a longitudinal assessment of volitional THC vapor SA across the lifespan in aged adult male and female rats. We expect females to recapitulate differences in THC/CBD intake and relapse as predicted in Aim 1. We also hypothesize that lifetime THC/CBD will negatively impact stress reactivity and spatial memory in aged adults, relative to those only exposed when aged. For both Aims 1 and 2, we expect that the biological endpoints collected from the hippocampus (lipids, RNA, protein) will reveal sex-, and age-, and exposure duration-specific changes in several targets related to endocannabinoid signaling and synaptic plasticity. Finally, in Aim 3, we will evaluate the impacts of volitional THC/CBD SA across the female reproductive cycle (pre-pregnancy, pregnancy, postpartum) on maternal behavior and relapse. We predict that THC/CBD SA will negatively impact maternal behavior. Furthermore, we will assess how pregnancy, and its associated changes in progesterone levels, will impact THC/CBD SA. We expect that females will reduce THC/CBD SA during gestation, inversely correlating with changes in progesterone, with a rebound increase in SA postpartum. We also hypothesize that THC/CBD SA will induce changes in the prefrontal cortex related to endocannabinoid signaling and synaptic plasticity. This project will significantly enhance our knowledge about how sex and age interact with THC/CBD to impact the brain and behavior across several vulnerable populations.