Review
Recovering from cocaine: Insights from clinical and preclinical investigations

https://doi.org/10.1016/j.neubiorev.2013.04.007Get rights and content

Highlights

  • Clinical and preclinical research both reveal neural adaptations cocaine abstinence.

  • Functional and structural changes occur in the cortex as well as subcortical dopamine systems.

  • The integrity of the prefrontal cortex is likely the best hallmark of extended abstinence.

  • There are some uniquely human aspects of abstinence that are difficult to model in abstinence.

Abstract

Cocaine remains one of the most addictive substances of abuse and one of the most difficult to treat. Although increasingly sophisticated experimental and technologic advancements in the last several decades have yielded a large body of clinical and preclinical knowledge on the direct effects of cocaine on the brain, we still have a relatively incomplete understanding of the neurobiological processes that occur when drug use is discontinued. The goal of this manuscript is to review both clinical and preclinical data related to abstinence from cocaine and discuss the complementary conclusions that emerge from these different levels of inquiry. This commentary will address observed alterations in neural function, neural structure, and neurotransmitter system regulation that are present in both animal models of cocaine abstinence and data from recovering clinical populations. Although these different levels of inquiry are often challenging to integrate, emerging data discussed in this commentary suggest that from a structural and functional perspective, the preservation of cortical function that is perhaps the most important biomarker associated with extended abstinence from cocaine.

Introduction

Chronic cocaine use is a seemingly intractable public health problem worldwide. Whether cocaine is snorted, injected, or smoked as crack, users often suffer serious negative consequences to their health, social relationships, as well as severe economic hardships. Although there have been many efforts to develop effective treatments, whether pharmacological or cognitive and behavioral, rates of relapse continue to be alarmingly high. Moreover, these relapse rates continue to be among the highest of all illegal drugs (Vocci, 2007). One substantial obstacle to the discovery of successful treatment approaches has been our rather incomplete understanding of the neurobiological processes that naturally occur when drug use is discontinued (likely best modeled in animals) as well as any unique features of the small population of addicts that are able to successfully abstain from cocaine for extended periods of time. Without a more complete picture of these structural and functional neuroadaptations, it is difficult to direct effective strategies toward targets with the greatest potential for promoting abstinence and reducing harm.

To understand the natural neural adaptations that follow discontinuation of drug use as well as neurological features that promote successful abstinence in humans, it is first necessary to understand the changes that directly result from cocaine exposure. Decades of robust molecular, genetic, cellular, and neural systems level studies have provided important insights in this area. One important approach that has been used in both human and animal models of chronic cocaine use is neuroimaging. This approach encompasses a wide range of in vivo and in vitro techniques capable of assessing neural function and structure, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), diffusion tensor imaging, tissue morphometry, metabolic mapping, and receptor autoradiography, among others. Not only do these approaches have the advantage of being able to sample multiple brain regions simultaneously, but many in vivo approaches can be applied to human drug users and animal models alike providing for substantial translation and cross-validation of findings. Here, we focus on the insights and perspectives that imaging approaches have contributed to the issues that surround the long-term neural adaptations that follow discontinuation of cocaine use after chronic abuse and dependence.

Although there are many unanswered questions, this brief commentary will consider two fundamental questions about abstinence from continued cocaine use that we believe neuroimaging studies can in part address:

  • (1)

    To what extent do the neurostructural and functional abnormalities that accompany chronic cocaine use either improve or persist following discontinuation of cocaine?

  • (2)

    Are there patterns of neural function or structure that can be used as predictors of successful abstinence when given the choice to use?

A broad perspective is required in order to address these questions. In this commentary we examine complementary insights from clinical addiction research and preclinical animal models of drug use. When considered together these data give us a deeper understanding of the neurofunctional and structural adaptations that are present in both early and extended periods of abstinence.

Section snippets

Imaging the brain of cocaine abstainers: clinical research

As with many psychiatric diseases, the neuropathology present in cocaine-dependent individuals is not restricted to a single brain region, a single cell type, or a single neurotransmitter system. Rather substance dependence is frequently associated with disruptions in at least three major systems that contribute to behavior – limbic processing, cognition, and basic motor control. These systems span both cortical and subcortical regions of the brain and therefore are vulnerable not only to

Investigating the consequences of abstinence from cocaine: preclinical research

There is no question that studies in human drug abusers, current and abstaining, can provide the best evidence about the course of this disorder. Among others, the ability to obtain verbal reports of the feelings engendered by the drug, factors that lead to drug use, the sources of drug craving, or the factors that lead to the motivation to quit, are among some of the obvious advantages of studies in human users. But there are many questions that cannot be readily answered, especially some of

Can we bridge preclinical and clinical research?

Throughout this commentary we have mentioned several ways in which well-controlled experiments in animal models of addiction can provide valuable interpretations for functional and structural findings from clinical research (i.e. extended exposure to cocaine leading to variability in the recovery of the dopamine rich striatum, and oligodendrocyte maturation as an explanation for elevated white matter in abstinence). There are at least two other promising lines of research however that we would

Conclusions

Here, we have presented a collection of findings (by no means intended to be exhaustive) from the perspectives of clinical and preclinical science in an attempt to answer two questions about the cessation of cocaine use after a prolonged history of drug use: (1) whether the neuroadaptations that result from cocaine exposure can reverse with abstinence, and (2) whether there are markers or neural signatures that can predict recovery. We have addressed these questions through examples from both

Acknowledgments

Funding for this work was provided by National Institutes of Health grants K01DA027756, DA09085 and DA06634. The authors received no compensation from other external organizations related to this manuscript and declare no competing financial interests.

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