The overall objective of this project is to use innovative animal models and imaging techniques to studyimpulsive behavior drug abuse. Experiments will yield information that will be directly translatable to humandrug abuse prevention and treatment. Brain imaging studies will allow us to examine underlyingneurobiological mechanisms and compare results to human brain imaging results. The main questions to beaddressed are whether impulsivity is related to excessive drug, food, and other substance use, and doesmagnetic resonance imaging (MRI) reveal neurobiological correlates with impulsivity and addiction? Groupsof rats will consist of those selected with a delay-discounting (DD) task for high (H) or low (L) impulsivity forcocaine (HiC, LoC) or food (Mil, Lol) and others will be selectively bred for high and low intake of a saccharinsolution (HiS, LoS). These groups will be compared on: 1) Cognitive impulsivity for cocaine or food basedon a DD task offering a choice between a larger delayed vs. smaller immediate reward, or motor impulsivity -impaired ability to inhibit motor action toward a cocaine or food reward (Go/No-go), 2) Escalation of cocaineself-administration, 3) Reinstatement of cocaine-seeking behavior (relapse), 4) Effectiveness of a GABArelatedtreatment drug, and 5) Preference for a sweetened liquid, a predictor of drug abuse.
The SpecificAims are: 1) To examine delay-discounting, as a factor contributing to drug abuse in male and female ratsand the addiction-prone (vs. resistant) phenotypes (HiC, LoC; Hil, Lol; HiS, LoS). Neuroimaging studies willbe conducted on the groups before exposure to cocaine to identify neurobiological mechanisms that areassociated with behavioral results, and results from the human studies (Projects 2 and 3), 2) To study motor(response inhibition) aspects of impulsive behavior in the addiction-prone and .Airesistant groups usingthe Go/No-go task that involves signaled Go (rewarded) and No-go (unrewarded) components. Respondingduring the No-go components represents failure of inhibitory control. These findings will be related to theimaging results and human studies (Projects 2 and 3), 3) To investigate differences in impulsivity-related,addiction-prone phenotypes in the escalation of cocaine intake, 4) To model reinstatement of drug-seeking todetermine how differences in impulsivity-related, addiction-prone phenotypes are translated to the mostchallenging aspect of drug abuse, relapse. 5) To examine the effects of treatment with topiramate, a GABArelateddrug, on cocaine self-administration in the impulsivity-related, addiction-prone, -resistant phenotypes(e.g., female, male; HiC, LoC; Hil, Lol; and HiS, LoS, respectively), and treatment success will be related tothe imaging results. These studies will allow us to relate impulsive behavior to several different aspects ofdrug abuse that are difficult to study in humans and to test treatments targeted at the GABA system.
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