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 diĜcult 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 inĚuence 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 conffirme