Difficulty suppressing or inhibiting pre-potent behaviors (one manifestation of 'impulsivity') has been linked with stimulant and alcohol abuse and dependence in humans and with addiction- like phenotypes in animal models. This relationship is thought to run in both directions; impulsivity is likely a liability factor for addctions, and the development of addiction erodes brain mechanisms involved in impulse control. This application relates to the former concern (that heritable variation in impulsivity leads to addictions) and test the idea that impulsive responding and sensitivity to the reinforcing effects of drugs of abuse are genetically correlated, meaning that a common set of genomic mechanisms influence both. This hypothesis will be tested directly, using a panel of classic inbred and recombinant inbred mice - the hybrid mouse diversity panel. We will examine cocaine self-administration in ~100 strains from the panel that will already have been studied for their ability to inhibit impulsive responding in a reversal learning test; in doing so, we will be ble to measure the genetic correlation between these traits. We will also conduct whole-genome scans for cocaine reinforcement using the gathered datasets. Completion of these experimental aims will offer an opportunity to undertake the first direct tests of the idea that impulsivity and addiction-like phenotypes are under common genetic control and will generate completely new information on the independent and common genetic loci that influence these behavioral traits. Understanding the biological mechanisms that index susceptibility to behavior addictions may illuminate new biomarkers for risk that can be used to assess the quality and impact of interventions, as well as to inform the development of new treatments for chemical and non- chemical dependencies.
Behavior addictions, including the abuse of or dependence on drugs of abuse, cause substantial personal and social costs. Unfortunately, prevention and cessation treatments are few and of limited efficacy. With that in mind, understanding the genetic architecture of risk for addictions raises new avenues, not just for quantifying liability, but for developing biomarkers that can be the target of prevention trials. Moreover, identification of the molecular genetic mediators of addictions raises new potential treatment targets.
