Genetic substrates of cue-reactivity and cocaine motivation

PROJECT SUMMARY Understanding the genetic factors that contribute to the transition from recreational to problematic drug use is vital for uncovering biological mechanisms that can aid in preventing and treating substance use disorders (SUDs). Genome wide association studies (GWAS) have been successful in identifying genetic variants, but validating these genes is diGcult given that human research is limited to non-invasive approaches. Other approaches include integrating GWAS results with large-scale ‘omics’ datasets, and conducting functional studies in animal models. One such model is the intermittent-access cocaine self-administration procedure (IntA), which triggers increased cocaine motivation (i.e., incentive sensitization) in rats after only limited amounts of drug exposure. This models the transition into early stages of SUD and, when compared to other procedures, can be used to dissociate total drug intake from incentive sensitization. To uncover the genetic factors behind incentive sensitization during IntA, our team has conducted a GWAS in a limited sample of heterogeneous stock rats and identiffied genomic regions that inEuence cocaine motivation and contain several candidate genes. Increasing the power of this study in Aim 1 will enable the discovery of additional gene variants contributing to the complex genetic landscape of SUD. Yet, candidate genes must be investigated with follow-up studies. In a separate project, multi-level ‘omics’ data (including GWAS results, phenome-wide association studies, and transcriptomics) were integrated to identify candidate gene variants underlying cue-reactivity, a trait that that is phenotypically and genetically correlated with measures of cocaine-cue reactivity. These candidates included the understudied genes Tenm4 and Far1. Subsequent behavioral neuroscience-based approaches established that administration of a Tenm4-associated peptide reduced several measures of cocaine motivation during IntA and thus conffirmed Tenm4's pleiotropic eeect on cocaine motivation and cue-reactivity. However, further characterization of Tenm4 and Far1 is needed, thus another goal of this project is to use CRISPR-based transcriptional manipulation to determine the roles of these genes in cocaine cue-reactivity and motivation (Aim 2). Finally, another approach for validating GWAS ffindings involves generating polygenic scores (PGSs) that can be used to predict cue-reactivity in naïve rats. In Aim 3, these PGSs will be used to determine the interaction between genetic vulnerability to cue-reactivity and changes in drug motivation during multiple cocaine self-administration paradigms. Thus, this project will enhance the understanding of genetic factors inEuencing SUD susceptibility, validate candidate genes, and determine how genetic predisposition interacts with drug exposure to produce addiction- like behaviors. These goals align directly with those of those of the NIDA Animal Genomics Program, that is, “to identify [genetic variants] that underlie … phenotypes associated with addictive behaviors … behaviors associated with SUD, [and] uncover the function of known or newly discovered genetic or epigenetic variants”.