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Title:Repeated amphetamine exposure and the enduring consequences on behavioral and neural plasticity
Author(s):Stanis, Jessica
Director of Research:Gulley, Joshua M.
Doctoral Committee Chair(s):Cohen, Neal J.
Doctoral Committee Member(s):Gulley, Joshua M.; Schantz, Susan L.; Galvez, Roberto
Department / Program:School of Molecular & Cell Bio
Discipline:Neuroscience
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):amphetamine
Adolescence
working memory
prefrontal cortex
delay-discounting
plasticity
Abstract:Amphetamines (AMPH) are relatively unique amongst the category of psychoactive drugs, as they are both prescribed for therapeutic purposes at an alarmingly increasing rate and abused illicitly on account of their potential pleasurable effects (World Drug Report, 2012). In adult subjects, chronic AMPH use is associated with deficits in decision-making (i.e., impulsivity) and working memory (e.g., Bechara et al., 1994; McKetin and Mattick, 1998; Rogers et al., 1999; Ornstein et al., 2000). However, not as much research exists about adolescent drug exposure and the long-lasting consequences on cognitive function in adulthood. We hypothesize that drug-induced changes in brain function are a major contributing factor to the behaviors that characterize addiction. In addition, drug exposure during a maturational time, such as adolescence, could have delayed and harmful consequences well after treatment has ceased. Thus, a major goal of this thesis was to examine the enduring effects of repeated AMPH exposure on cortical function and cognitive behavior. The experiments presented here were designed using methods very sensitive to prefrontal cortex (PFC) function. In experiment 1 (Chapter 5), single-unit recordings from actively behaving rats were used to examine the relationship between the locomotor response (i.e., the ability to induce sensitization) and medial PFC (mPFC) firing activity to repeated AMPH treatment. The results suggested that repeated AMPH led to very selective changes in mPFC function when behavioral sensitization was present. Specifically, the magnitude of excitatory responses increased with the development of sensitization but was less persistent with a maximal sensitized response. In experiment 2 (Chapter 2), the relationship between behavioral sensitization and impulsive choice behavior (operant delay-discounting) was examined in rats that received prior, repeated AMPH treatment. Chronic exposure to AMPH did not cause rats to become more impulsive. However, long-lasting changes in AMPH-induced locomotor activity were observed. The results suggested that the neuroadaptations associated with behavioral sensitization did not cause enduring deficits in the aspects of cognition that the delay-discounting task requires. In experiment 3 (Chapter 3), we examined whether impulsivity might be a pre-existing trait by using an established model that is based on an initial drug response to a low dose of cocaine. The results suggested that differential sensitivity to cocaine-induced locomotion was predictive of impulsivity, and the potential differences could shed light into mechanisms contributing to the vulnerability for addiction. In experiment 4 (Chapter 4), we took a multi-faceted approach to examine long-lasting consequences of chronic AMPH exposure on working memory function. We had three main factors in mind: method of drug exposure (repeated, intermittent versus escalation-binge), age of drug exposure (adolescence versus adulthood), and the initial sensitivity of a psychostimulant. While adolescent-treated rats were found to be less sensitive to the stereotypy-inducing effects of both the intermittent and escalation-binge methods than adult-treated rats, they were more vulnerable to exposure-induced learning and memory impairments as tested in adulthood. Interestingly, the age-related deficits agree with the equal, but opposite model of drug action. That is, the intermittent regimen impaired working memory in adolescent-treated and not adult-treated rats, whereas the escalation-binge regimen impaired working memory in adult-treated and not adolescent-treated rats. In addition, the delay dependent deficits in adolescent- and adult-exposed rats were predicted based on their initial sensitivity to a single injection of cocaine. In the experiments presented here, repeated exposure to AMPH was found to have long-lasting consequences on learning and memory processes. These deficits were associated with initial differences in cocaine-induced locomotor activity. Moreover, the deficits were dependent on both the age and method of drug exposure. Taken together, our findings suggest that particular populations of neurons are more vulnerable to AMPH-induced changes. This notion is key in interpreting findings that suggest sensitizing regimens of AMPH do not necessarily lead to long-lasting changes in behavioral tasks that are sensitive to changes in PFC function. Furthermore, focusing on pathway-specific changes, especially within a neurodevelopmental framework, will be key in future studies if we want to understand individual vulnerabilities to psychiatric disorders such as addiction.
Issue Date:2013-05-24
URI:http://hdl.handle.net/2142/44430
Rights Information:Copyright 2013 Jessica Stanis
Date Available in IDEALS:2013-05-24
2015-05-24
Date Deposited:2013-05


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