Nicholas W. Simon - US grants

[unreadable] DESCRIPTION (provided by applicant): It is well-established that drug abuse is associated with high levels of impulsivity and impaired decision making. This behavior may contribute to addiction by rendering drug abusers more likely to choose the short-term rewards of further drug use over the delayed rewards of abstinence (such as health, employment, and family). Impulsive behavior in drug abusers is associated with structural and functional changes in the orbitofrontal cortex, a frontal lobe brain structure that is critical for decision making and impulse control. However, the degree to which these alterations are caused by drug abuse as opposed to acting as predisposing factors for drug abuse remains unclear. This issue must be addressed to provide a better understanding of addictive processes and ultimately aid in development of treatment strategies for addiction. The overall goal of this research program is to determine the behavioral and neurobiological mechanisms by which exposure to drugs of abuse causes long-lasting deficits in impulsive choice. Behavior will be assessed via a delay discounting task in which rats must choose between a small, immediate reward and a large, delayed reward. Impulsivity in this model is defined as increased preference for the small reward over the large delayed reward. Preliminary data demonstrate that a relatively brief period of cocaine exposure causes increased impulsive choice that is evident as long as 3 months after cocaine cessation. Specific Aim 1 will determine the minimum dose of cocaine necessary to replicate this effect, as well as the duration of cocaine's effects on impulsive choice. Specific Aim 2 will use expression of the immediate early gene product c-Fos to determine how previous cocaine exposure alters neural activity in the orbitofrontal cortex, and whether such neurobiological alterations are related to impulsive choice behavior in the delay discounting task. Specific Aim 3 will involve the administration of the dopaminergic antagonist a-flupenthixol prior to the delay discounting task in cocaine-exposed rats. Excessive dopamine transmission in the orbitofrontal cortex (which seems to result from cocaine pre-exposure) appears to be related to high levels of impulsivity; therefore, this treatment is expected to reduce impulsive choice behavior in these subjects. This research will offer valuable information regarding the long term effects of cocaine exposure on behavioral and neurobiological aspects of impulsive choice behavior, as well as a treatment that may reverse these effects. Considering the prominence of drug-abuse in modern society, it is important to develop a thorough understanding of how drugs can impact the brain and cognition. Such information will be critical for controlling and/or treating drug addiction and the long-term debilitating effects of drug abuse. [unreadable] [unreadable] [unreadable]