Review
Striatal ups and downs: Their roles in vulnerability to addictions in humans

https://doi.org/10.1016/j.neubiorev.2013.01.018Get rights and content

Abstract

Susceptibility to addictive behaviors has been related to both increases and decreases in striatal function. Both profiles have been reported in humans as well as in animal models. Yet, the mechanisms underlying these opposing effects and the manner in which they relate to the behavioral development and expression of addiction remain unclear. In the present review of human studies, we describe a number of factors that could influence whether striatal hyper- or hypo-function is observed and propose a model that integrates the influence of these opposite responses on the expression of addiction related behaviors. Central to this model is the role played by the presence versus absence of addiction related cues and their ability to regulate responding to abused drugs and other rewards. Striatal function and incentive motivational states are increased in the presence of these cues and decreased in their absence. Alternations between these states might account for the progressive narrowing of interests as addictions develop and point to relevant processes to target in treatment.

Highlights

► Both increases and decreases in striatal function have been related to susceptibility to addiction. ► We describe a number of factors that could influence whether striatal hyper- or hypo-function is observed in humans. ► A model of addiction is proposed that integrates the influence of these opposite responses. ► Central to this model is the role played by the presence versus absence of addiction related cues.

Introduction

Two frequently contrasted theories propose that the development of addiction related behaviors reflects the hyper- versus hypo-activation of limbic reward systems. The debate is not new (e.g., Wikler, 1948, Wikler, 1973, Vogel et al., 1948). Nor are the positions irreconcilable. Recent evidence raises the possibility that the expression of hyper- versus hypo-active incentive motivational states might reflect, in significant part, the presence versus absence of addiction related cues (Leyton and Vezina, 2012; see also Anagnostaras and Robinson, 1996, Anagnostaras et al., 2002, Stewart and Vezina, 1988, Stewart and Vezina, 1991, Vezina and Leyton, 2009). The present review focuses on the evidence for these alternating states in humans, the possibility that individuals may differ in their susceptibility to them, and the role that addiction related cues play in their expression. Although considered in the human clinical setting, many of the ideas discussed here have been tested over the last thirty years in some detail in preclinical drug sensitization experiments. The processes identified in these studies could have particular bearing for our understanding of the role played by addiction related cues in the generation of subjective and behavioral states in humans. We thus begin with a brief review of this literature before turning to a systematic treatment of the evidence in humans.

Section snippets

Preclinical studies in laboratory animals

Psychostimulant drugs like amphetamine, cocaine, and nicotine have long been known to produce their behavioral activating and motivating effects by stimulating the mesoaccumbens dopamine (DA) system. Many preclinical studies, mostly in rodents, have studied the effects of repeated exposure to these drugs on biochemistry and behavior. Of the different consequences of drug exposure assessed, two have emerged that have particular relevance for our understanding of excessive drug taking: the

Effects of cues

In substance abusers, exposure to stimulant drug associated cues elicits a wide range of subjective, behavioral and physiological responses (Carter and Tiffany, 1999, Childress et al., 1988, O’Brien et al., 1990). That these responses are drug-like is consistent with their ability to elicit incentive motivational states associated with the drug (Stewart et al., 1984, Robinson and Berridge, 2003)1

Effects of cues

Exposure to reward related events consistently activates the striatum in healthy humans (Knutson and Cooper, 2005). This has been studied in greatest detail in relation to monetary reward. In these studies, numerous types of stimuli are presented. These include (i) familiar cues that subjects already know are associated with the presence or absence of rewards, (ii) previously neutral cues that subjects learn about during the study, (iii) cues indicating that a reward will be presented either

Subjects at risk for addictions: striatal activations

Groups of individuals can be categorized according to their risk for addiction. Among the best established predictors are (i) a dense family history of substance use problems (Dawson et al., 1992, Merikangas et al., 1998, Stoltenberg et al., 1998), (ii) externalizing behavioral characteristics and impulsive, sensation seeking personality traits (Krueger, 1999, Kendler et al., 1997, Kendler et al., 2003, Tarter et al., 2003), and (iii) subjective and behavioral responses to a drug challenge (

Effects of cues

Two recent meta-analyses independently concluded that the striatum is consistently activated by exposure to drug-related cues in subjects meeting diagnostic criteria for substance use disorders (Chase et al., 2011, Tang et al., 2012). These responses are stable (Schacht et al., 2011) and elevated, as compared to non-substance abusers. For example, compared to light social drinkers, dependent drinkers have been reported to exhibit greater alcohol cue-induced striatal activation (Vollstädt-Klein

Subjects with non-substance addictions – gambling and binge eating disorders: striatal activations

Gambling (Frascella et al., 2010, Leeman and Potenza, 2012) and binge eating disorders8 (Davis et al., 2011,

Conclusions: treating the striatum – boost or block?

Addictions are complex, multi-factorial, and heterogeneous in origin and expression. The factors discussed in the present review will not account for all facets of the disease. At the neurobiological level alone, addictions involve more brain regions than the striatum and more neurotransmitters than DA. Nonetheless, the current view describes processes that can account for much of the variability in the literature. It can also improve our understanding of the role of addiction related cues in

Acknowledgements

This review was made possible by grants from the Canadian Institutes for Health Research (MOP-36429 and MOP-64426, ML) and the National Institutes of Health (DA09397, PV). We dedicate this review to Ann Kelley. Her boundless energy, her love of life, and deep knowledge and passion for her work made her a role model for all of us.

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