PRECLINICAL STUDIES:ANIMAL MODELS OF IMPULSIVITY AND ADDICTION

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The overall objective of this project is to use innovative animal models and imaging techniques to study impulsive behavior drug abuse. Experiments will yield information that will be directly translatable to human drug abuse prevention and treatment. Brain imaging studies will allow us to examine underlying neurobiological mechanisms and compare results to human brain imaging results. The main questions to be addressed are whether impulsivity is related to excessive drug, food, and other substance use, and does magnetic resonance imaging (MRI) reveal neurobiological correlates with impulsivity and addiction? Groups of rats will consist of those selected with a delay-discounting (DD) task for high (H) or low (L) impulsivity for cocaine (HiC, LoC) or food (Mil, Lol) and others will be selectively bred for high and low intake of a saccharin solution (HiS, LoS). These groups will be compared on: 1) Cognitive impulsivity for cocaine or food based on 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 cocaine self-administration, 3) Reinstatement of cocaine-seeking behavior (relapse), 4) Effectiveness of a GABArelated treatment drug, and 5) Preference for a sweetened liquid, a predictor of drug abuse. The Specific Aims are: 1) To examine delay-discounting, as a factor contributing to drug abuse in male and female rats and the addiction-prone (vs. resistant) phenotypes (HiC, LoC; Hil, Lol; HiS, LoS). Neuroimaging studies will be conducted on the groups before exposure to cocaine to identify neurobiological mechanisms that are associated 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 using the Go/No-go task that involves signaled Go (rewarded) and No-go (unrewarded) components. Responding during the No-go components represents failure of inhibitory control. These findings will be related to the imaging 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 to determine how differences in impulsivity-related, addiction-prone phenotypes are translated to the most challenging aspect of drug abuse, relapse. 5) To examine the effects of treatment with topiramate, a GABArelated drug, 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 to the imaging results. These studies will allow us to relate impulsive behavior to several different aspects of drug abuse that are difficult to study in humans and to test treatments targeted at the GABA system.