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Sensitivity to cocaine and its associated stimuli ("cues") are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-induced relapse of drug-seeking. Whereas each of these traits has established links to drug use, the relatedness between the individual traits themselves has not been well characterized in preclinical models. To this end, the propensity to attribute incentive salience to a food cue was first assessed in two distinct cohorts of 2716 outbred heterogeneous stock rats (HS; formerly N:NIH). We then determined whether each cohort was associated with performance in one of two paradigms (cocaine conditioned cue preference and cocaine contextual conditioning). These measure the unconditioned locomotor effects of cocaine, as well as conditioned approach and the locomotor response to a cocaine-paired floor or context. There was large individual variability and sex differences among all traits, but they were largely independent of one another in both males and females. These findings suggest that these traits may contribute to drug-use via independent underlying neuropsychological processes.

ObjectiveObesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits.MethodsThis study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers.ResultsThis study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci.ConclusionsThis study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing.

There are a number of traits that are thought to increase susceptibility to addiction, and some of these are modeled in preclinical studies. For example, "sensation-seeking" is predictive of the initial propensity to take drugs; whereas "novelty-seeking" predicts compulsive drug-seeking behavior. In addition, the propensity to attribute incentive salience to reward cues can predict the propensity to approach drug cues, and reinstatement or relapse, even after relatively brief periods of drug exposure. The question addressed here is the extent to which these three 'vulnerability factors' are related; that is, predictive of one another. Some relationships have been reported in small samples, but here a large sample of 1,598 outbred male and female heterogeneous stock rats were screened for Pavlovian conditioned approach behavior (to obtain an index of incentive salience attribution; 'sign-tracking'), and subsequently tested for sensation-seeking and novelty-seeking. Despite the large N there were no significant correlations between these traits, in either males or females. There were, however, novel relationships between multiple measures of incentive salience attribution and, based on these findings, we generated a new metric that captures "incentive value". Furthermore, there were sex differences on measures of incentive salience attribution and sensation-seeking behavior that were not previously apparent.