The effects of cocaine: A shifting target over the course of addiction

Abstract

Repeated exposure to psychostimulant drugs such as cocaine has been shown in numerous studies to produce significant neuroadaptations in both structure and function throughout the brain. Nonhuman primate models provide a way to systematically evaluate these adaptations engendered by cocaine self-administration and simulate the progressive nature of cocaine addiction in humans. Functional activity, measured using the 2-[¹⁴C]deoxyglucose method, was evaluated at selected critical time points over the course of chronic cocaine self-administration in rhesus monkeys. The effects of cocaine exposure in the initial stages of self-administration resulted in changes in functional activity in a highly restricted network of interconnected brain regions when compared to activity in food-reinforced controls. This pattern of changes was confined mainly to ventromedial prefrontal cortex and ventral striatum. Following chronic exposure to cocaine self-administration, however, the spatial extent and intensity of significant alterations in functional activity expanded considerably. The shift in topography of these changes was orderly, originating ventromedially in the prefrontal cortical-ventral striatal network and expanding dorsally to encompass the dorsal striatum. A strikingly similar progression occurred within the cortical areas that project to each of these striatal regions. Preliminary studies suggest that this pattern is maintained despite periods of abstinence from cocaine. The shifting patterns of cerebral metabolic function that accompany longer durations of cocaine self-administration may underlie many of the characteristics of chronic drug exposure, and may provide transitional mechanisms to more compulsive cocaine use.

Introduction

Cocaine users are frequently characterized as suffering from a variety of cognitive impairments and affective dysfunction. Cognitively, these may include deficits in decision-making, abstract reasoning, and nonverbal problem solving (Hoff et al., 1996, Manschreck et al., 1990, Rogers and Robbins, 2001). In terms of affective dysfunction, cocaine users have a high incidence of depressive disorders, attention deficit disorder, and other psychopathologies (Carroll et al., 1994, Clure et al., 1999, Kilbey et al., 1992, Levin et al., in press). Paralleling these alterations in affect and cognition, there are widespread structural and functional brain abnormalities associated with chronic cocaine use. Rates of cerebral metabolism assessed with PET, and changes in blood flow measured with fMRI and PET, are significantly lower in chronic cocaine users when compared to those of healthy control subjects, particularly in the prefrontal cortex and thalamus (Goldstein and Volkow, 2002; for review see Volkow et al., 2004). Furthermore, poor performance on response inhibition tasks (Goldstein et al., 2001, Kaufman et al., 2003) and working memory tasks (Hester and Garavan, 2004), both known to involve processing in prefrontal cortex, is associated with abnormal activation patterns in a network of cortical and subcortical areas including the caudate and thalamus, as well as cingulate, premotor, orbitofrontal, medial prefrontal, and insular cortices. Decreases in the structural integrity in prefrontal white matter (Lim et al., 2002) and gray matter density in distributed frontal and temporal cortical regions (Franklin et al., 2002) also occur in chronic cocaine users.

These studies of human drug addicts often imply or assume that cocaine exposure is the cause of these deficits. However, it is difficult to exclude the influence of other factors such as the use of other illegal and legal drugs, co-morbid psychiatric conditions, differences in lifestyle, etc. Further complications arise from the considerable differences across studies in inclusion criteria for drug use and abstinence, as well as the fact that self-reports of history and patterns of drug use in human subject are frequently unreliable and certainly highly variable. Perhaps most important, is the difficulty in assessing whether any of these changes occur as a result of drug exposure or pre-date any drug experiences. Because of these and many other problems, it is virtually impossible to isolate and address the issue of the consequences of chronic cocaine exposure in human populations. Therefore, one question remains largely unanswered: Does chronic cocaine use in and of itself have a major impact on brain activity? This is a central question, not only for treatment and recovery from addiction, but also for prevention as well.