Multiscale Insights into the Epigenetic Basis of THC Consumption

Project Summary The United States is in the midst of a significant paradigm shift around the perception and use of cannabis. The majority of states now permit recreational or medical use, reflecting a shift in views of cannabis with many believing the drug is not harmful or addictive. Despite the rise in these beliefs, repeated large-scale reports show that 10-30% of regular users meet the criteria for cannabis use disorder (CUD), an addictive disorder characterized by loss of control over use and relapse. As cannabis becomes more broadly available, it is essential that we determine the foundational mechanisms that drive problematic use. A major obstacle in studying CUD has been the lack of preclinical models of drug use. To bridge this gap, we have implemented a translational model of volitional edible ∆-9-tetrahydrocannabinol (THC; the main psychoactive constituent in cannabis) consumption to assess drug taking and seeking. With this paradigm we observed that unlike intravenous self-administration models, rats readily consume THC gelatin. Critically, this model recapitulates drug taking and cognitive phenotypes observed in CUD including increased drug intake and cue-induced seeking in males as well as individual differences in the capacity to titrate intake. This model provides a powerful foundation to assess neurobiological mechanisms that drive CUD-like behavior. Such clear sex and individual differences suggest potential involvement of epigenetic factors contributing to these phenotypes. Drugs of misuse like cannabis induce changes in epigenetic mechanisms such as histone modifications (e.g. methylation) which impact the accessibility of chromatin, permitting or suppressing gene expression. These mechanisms can activate or inhibit molecular machinery underlying synaptic plasticity leading to addiction-like behaviors. Recent clinical data indicate cannabis use is associated with changes in DNA methylation, and animal models have demonstrated a causal impact of THC exposure on epigenetic substrates throughout the mesocorticolimbic system. Using unbiased RNA sequencing of the nucleus accumbens core (NAcC), a reward subregion implicated in addiction, we observed dysregulation of transcripts underlying synaptic plasticity associated with changes in histone methylation. Although epigenetic mechanisms are a promising target for mitigating addictive behaviors, these mechanisms are tightly coordinated in a cell-type specific manner which can influence phenotypes. To improve the development and translation of novel therapeutics for addictions like CUD that target epigenetic mechanisms, it is essential we develop a cell-type specific understanding of the recruitment and role of these mechanisms in problematic cannabis use. This award will be used to interrogate the impact of histone methylation of distinct NAcC neuron outputs on the transcriptome, calcium activity, and regional networks. This program will be the first to show the causal impact of epigenetic modifiers on behaviors that promote and maintain CUD and will provide critical insight into novel therapeutic targets.