Center for Genetic Studies of Drug Abuse in Outbred Rats

Overview

Cigarette smoking caused 480,000 deaths annually, making nicotine about 10 times more lethal than opioids. In addition to the loss of life, smoking-related illness in the United States cost more than $300 billion each year. Smoking is influenced by both environmental and genetic factors. The strong influence of social environment in smoking initiation is well-documented, especially during adolescence. At least 26 genome wide association studies (GWAS) on smoking have been conducted to date. However, the genetic factors influences smoking remains largely unknown. We have developed a rat model of nicotine intravenous self-administration in adolescent rats that captures the role of social learning in promoting nicotine intake. This operant licking model delivers intravenous nicotine with a contingent oral flavor cue. Two signals transmitted from a conspecific (the nicotine associated odor cue and carbon disulfide, a component of rodent breath) facilitates the extinction of nicotine conditioned aversion and promotes nicotine intake. In the first funding period, we have phenotyped close to 1,600 adolescent heterogenous stock rats (both males and females) on this model as well as a few behavior traits measuring social and anxiety related traits. Our regression analysis on the behavioral data showed that social and emotional traits explains approximately 30% of the variance in nicotine intake. Our genetic analysis has identified many quantitative trait loci for the behavioral phenotypes. Human GWAS has shown that increasing sample size has exponentially increases the number of significant associations. We therefore propose to extend our study by phenotyping another 1,600 rats. We anticipate the combined study will identify genes involved in different aspects of nicotine addiction, including its rewarding and aversive effects, propensity to be acquire behavior from a peer, and relapse, etc. This renew in general follows the experimental design of our existing protocols, with the exception that we will add a new social interaction test, where we will use a video analysis pipeline recently developed in our lab that uses artificial intelligence to analyze the social behavior of freely moving rats. In Aim 1, we’ll phenotype adolescent heterogeneous rats. We’ll receive breeders from Core B and generate 400 adolescent rats per year (1,600 rats for the project). These rats will first be phenotyped for their social behavior, novelty seeking and anxiety-like behaviors. They then will be implanted with a jugular catheter and start nicotine IVSA on postnatal day 38. In Aim 2, We will analyze the relationships between behavioral traits using regression, genetic correlation, and Phenome-wide associations (PheWAS). In Aim 3, we will obtain naive brain tissues for a brain region specific transcriptome database.