Elsevier

NeuroImage

Volume 28, Issue 4, December 2005, Pages 904-914
NeuroImage

Neural responses to acute cocaine administration in the human brain detected by fMRI

https://doi.org/10.1016/j.neuroimage.2005.06.039Get rights and content

Abstract

An improved functional MRI (fMRI) method for the reduction of susceptibility artifacts has been utilized to measure blood oxygen level-dependent (BOLD) responses to acute cocaine administration in the human brain of cocaine users. Intravenous administration of cocaine (20 mg/70 kg) activated mesolimbic and mesocortical dopaminergic projection regions and showed temporal positive or negative BOLD responses. These results obtained from human cocaine users supported the involvement of the dopaminergic pathway in cocaine addiction from animal models. In addition, the cocaine administration also induced activations in the hierarchical brain networks in the anterior prefrontal cortex (aPFC) of the Brodmann area 10 (BA10) and orbitofrontal cortex (OFC). It is suggested that the dopaminergic pathways and the hierarchical brain networks may participate in mediating cocaine reward processes, associative learning, motivation, and memory in cocaine addiction in the human brain.

Introduction

Understanding the neurobiological processes responsible for the altered control that drives drug-taking behavior is a central challenge in addiction research. Loss of control, a phrase often employed to describe compulsive drug intake and drug seeking, despite the presence of adverse consequences, clearly does not connote the absence of cognitive control. Rather, a drug addict's motivated behavior is likely to be highly manipulated by a powerful desire for the drug. However, it is far from clear how repeated drug use alters normal brain control systems, and which neural systems are responsible for the addiction behavior. During the last decade, substantial converging evidence has suggested that many, if not all, drugs of abuse recruit the mesocorticolimbic (MCL) dopamine (DA) system as a major neural substrate for the mediation of their reinforcing effects (Koob and Bloom, 1988, Porrino et al., 1988, Woolverton and Johnson, 1992, Volkow et al., 1997, Wise, 1998). Yet, reinforcement or reward processing alone cannot explain compulsive drug use and loss of control (Volkow et al., 2000).

Jentsch and Taylor (1999) proposed that this behavior is a result of the synergism of two distinct phenomena: enhancement of the conditioned reinforcing effects of drug-associated stimuli associated with dysfunction of the limbic system, and impairment of inhibitory control tied to dysfunction of the prefrontal cortex. Such an interaction may characterize impulsive drug abuse as a disease of the frontostriatal system. Based on data from a series of positron emission tomography (PET) studies involving psychostimulants and regular cocaine abusers, Volkow and Fowler (2000) interpreted the alteration of the brain control system as a disruption of the striato–thalamo–orbitofrontal (STO) circuitry, leading to the conceptualization of drug addiction as a syndrome of impaired response inhibition and enhanced salience attribution (Goldstein and Volkow, 2002). Drug addiction has also been viewed as a dopamine-dependent associative learning disorder (Di Chiara, 1999). Recently, an extensive review presented evidence that the process of drug addiction shares striking commonalities with neural plasticity associated with reward learning, motivation, and memory (Kelley, 2004). Still, it is not clear why drugs of abuse are consistently selected over other types of rewards. Clinical observations indicated that bingeing cocaine abusers continue to use cocaine without satiety even when the drug no longer produces rewarding effects (Fischman and Foltin, 1992, Volkow et al., 2003).

Neuroimaging studies of the acute effects of cocaine, an exceptionally reinforcing and addictive drug of abuse (Gavin and Ellinwood, 1988), in cocaine-dependent humans offers a possibility of meeting some of these challenges. Past investigations have stressed a need to identify the brain regions sensitive to acute cocaine administration and describe both the temporal characteristics of cocaine action and the interaction between affected neural circuits (Porrino et al., 2002). Pioneering research employed functional magnetic resonance imaging (fMRI) and PET to investigate candidate neural systems responsible for mediating the psychoactive effects of cocaine in the human brain (Wallace et al., 1996, Breiter et al., 1997), but the technical limitations of these techniques prevented investigation of important components. Limited spatial resolution did not allow the PET method to detect activity in the nucleus accumbens (NAc), a site considered to be a center of reward processing in humans and animals (Wise, 2002). The fMRI study (Breiter et al., 1997) reported activation in the prefrontal and cingulate areas, but did not investigate the activity in the anterior prefrontal cortex (aPFC) and orbitofrontal cortex (OFC)—brain regions often associated with memory, motivation, and behavioral control. The presence of a severe background gradient in these areas, which reside adjacent to air-tissue boundaries, causes magnetic susceptibility changes. This static gradient produces two well-known artifacts, signal dropout and image distortion (Jezzard and Balaban, 1995, Devlin et al., 2000, Merboldt et al., 2001), which significantly impair the reliable detection of neural activity in these brain regions. To fill this gap, we have developed a MultiEcho Segmented EPI with z-shimmed BAckground gradient Compensation (MESBAC) pulse sequence (Li et al., 2002). The MESBAC sequence significantly reduces the susceptibility-induced artifacts, robustly detects the blood oxygenation level-dependent (BOLD) signal and provides accurate image registration over a limited number of slices. In the present paper, we employed this new fMRI technology to confirm the hypothesis that acute cocaine administration concurrently activates the mesolimbic and mesocortical dopaminergic projections, which in turn gate the hierarchical brain networks that mediate associative learning, motivation and memory.

Section snippets

Human subjects and drug run-up

Fifteen right-handed, nontreatment seeking regular cocaine abusers from the greater Milwaukee area (12 black, two white, and one Hispanic), of which eight were male, participated in this study. Besides cocaine addiction, occasional marijuana use, and regular use of cigarettes, the subjects were not users of controlled substances or psychiatric medications. Additionally, subjects were screened for the presence of major psychiatric or neurologic illnesses, claustrophobia, alcoholism, peripheral

Cocaine administration has induced significant “High” and “Craving” ratings

Among the experimental participants, visual analog scales (VAS) during acute cocaine experiments were obtained from nine subjects. Fig. 1 shows the time courses of the mean VAS ratings for high (A) and craving (B). These ratings sustained postinfusion increases above their respective preinfusion baselines during the cocaine runs. The high rating reached its peak 3–4 min after postinfusion, whereas the craving rating reached its height 5–7 min after postinfusion. Both high and craving rating

Two major findings

By correcting the through-plane susceptibility gradients with the MESBAC pulse sequence, we could test the hypothesis that intravenous cocaine administration activates the mesolimbic and mesocortical dopaminergic circuits. Our first finding is that acute cocaine administration not only activated the mesolimbic dopaminergic regions (VTA, NAc, SCC, BF/VP, PHG, and Amy), but also the orbitofrontal and anterior prefrontal cortices. Although cocaine exerts a complex effect on neural activity and

Acknowledgments

This work was supported by the National Institute on Drug Abuse Grant DA10214 and General Clinical Research Center Grant RR00058, and by the Keck Foundation. We thank Ms. Trish Barribeau and Ms. Carrie O'Connor for editorial assistance.

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