Striatal ups and downs: Their roles in vulnerability to addictions in humans (2013)

Marco Leyton^a,** and Paul Vezina^b,*

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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.

3.1. 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.

The elicited states include a narrowing of attentional focus toward the rewards and an increased propensity to pursue and approach them. The critical processes associated with activity in the striatum need not necessarily be conscious (Fischman, 1989; Tiffany, 1990; Lamb et al., 1991; Winkielman et al., 2005; Childress et al., 2008; Field et al., 2009; Perkins, 2009; Berridge, 2012; Waters et al., 2012); conscious craving may be more closely related to activity in cortical structures (Goldstein et al., 2009; de Lange et al., 2011). Nonetheless, self-reported craving is a commonly used proxy and ecological momentary assessments acquired with real-time electronic diaries confirm that exposure to drug cues, and their elicitation of craving states, commonly occur in the minutes and hours before new bouts of stimulant drug use (Epstein et al., 2009). Similarly, in laboratory studies, craving and reward-seeking behavior have been reported to increase following exposure to cues associated with amphetamine (Culbertson et al., 2010; Tolivar et al., 2010), cocaine (Childress et al., 1988, 1993), alcohol (George et al., 2001; Bragulat et al., 2008), cigarettes (Droungas et al., 1995; Carter and Tiffany, 2001; Wray et al., 2011), heroin (Fatseas et al., 2011; Zhao et al., 2012a), and natural rewards such as food (Jansen, 1998; Kelley and Berridge, 2002; Mahler and de Wit, 2010) and sex (Conaglen and Evans, 2006; Kim and Zauberman, in press).

Cues have more potent effects when subjects know that there will soon be an opportunity to use the drug (Carter and Tiffany, 2001; Dar et al., 2005; Juliano and Brandon, 1998). These, of course, are the usual circumstances under which the cues appear in the natural environment. A striking illustration of this phenomenon was recently reported in flight attendants. Smokers on either short (3–5.5 h) or long flights (8–13 h) developed cigarette cravings toward the end of the trip. Cravings at the end of the short flight were as strong as cravings at the end of the long flight and substantially higher than those seen at the shorter time-point during the long flight (Dar et al., 2010).

Drug related cues can also elicit behavioral effects. These include conditioned place preferences (Childs and de Wit, 2009, in press) and attentional biases (Cox et al., 2006; Hogarth et al., 2008; Field et al., 2009; Little et al., 2012), conditioned reinforcement (Foltin and Haney, 2000), accelerated initiation of drug use (Herman, 1974), as well as increased drug seeking (Panlilio et al., 2005; Hogarth et al., 2007) and self-administration (Herman, 1974; Droungas et al., 1995; Mucha et al., 1998; Hogarth et al., 2010).

3.2. Effects of drugs

As discussed above, a large animal literature indicates that the repeated administration of abused drugs can alter their effects. In humans, the best established change observed following repeated drug exposure has been transient tolerance to the subjective effects of stimulants (Brauer et al., 1996) and to the depressant effects of opiates and benzodiazepines (Hug, 1972)². By comparison, the possibility that drug sensitization might occur in humans has been considered more controversial. Initial evidence came from observations made in the U.S. and Japan following the Second World War during episodes of heightened abuse of amphetamine-like drugs. Retrospective histories from this period suggested that repeated exposure to high doses of amphetamines (typically 100 mg or more) could lead to psychotic symptoms, including hallucinations and delusions (Connell, 1958; Ellinwood, 1967; Griffith et al., 1972; Sato, 1992; Sato et al., 1992). These effects could be reproduced in laboratory settings (Angrist & Gershon, 1970; Bell, 1973). The time course leading to the first psychotic episode was found to vary between individuals, an effect possibly related to dose, frequency of use, the co-abuse of other substances, and the presence of pre-existing vulnerability traits. Strikingly, periods of substance abuse were followed in some individuals by a long-lasting susceptibility to the re-emergence of psychotic symptoms after re-exposure to a much lower dose of the drug (Sato, 1992; Sato et al., 1992).

Although intriguing, the above reports did not provide direct experimental evidence that repeated drug exposure could produce sensitization-like phenomena in humans. This evidence has been reported only more recently. In six of seven controlled laboratory studies in which participants received a minimum of 20 mg (p.o.) of d-amphetamine per session, sensitization of the drug’s energizing effects was observed (Table 1). In the most recent study, evidence that this effect could come under environmental control was also seen. Subjects who received two doses of d-amphetamine in the same room reported a sensitized response to the second dose whereas those who received the second dose in a distinctively different room showed, if anything, evidence of tolerance (Childs and de Wit, in press).

  

Table 1

Dose-dependent development of sensitized responding to repeated d-amphetamine in healthy human subjects.

It is noteworthy that the time courses for sensitization- and tolerance-like phenomena are different³. Whereas sensitization is a long-lasting, possibly even permanent phenomenon (Robinson and Becker, 1986; Boileau et al., 2006), tolerance is more transient (Vogel et al., 1948; Hug, 1972; Brauer et al., 1996). Indeed, a major precipitant of drug overdose and mortality stems from the ability of drug seeking states to be elicited long after tolerance has dissipated (Merrall et al., 2010).

3.3. Effects of cues and cues + drugs in different subject populations

In the sections below, we review the effects of drug cues and cues plus drugs. These effects are examined separately in healthy subjects without addictions, in subjects at risk for addictions, and in subjects with substance use disorders. Distinguishing between these populations is necessary as drugs and drug cues elicit different effects in different individuals. Since the effects of both acute and repeated drug exposure can interact with the particular characteristics an individual presents, they can provide insights into the factors that regulate the development and expression of motivated behaviors directed at obtaining and self-administering drugs of abuse. Indeed, as often noted, only some of the individuals who experiment with drugs develop a substance use disorder (Tsuang et al., 1998; Zinkernagel et al., 2001; Anthony, 2002; Agrawal et al., 2012; Kendler et al., 2012). Factors that have been identified to influence progression to addiction include personality traits (Ayduk et al., 2000; Conrod et al., 2000; Tarter et al., 2003), early life histories (Hyman et al., 2006; Enoch et al., 2010), ever-changing socio-cultural norms (Nutt, 2012), individual differences in drug specific metabolic enzymes (Ferguson and Tyndale, 2011), and additional heritable factors with unclear mechanisms. An implication of these observations for the study of addiction and addiction related processes is the need to identify and characterize effects that might occur preferentially within a subset of individuals (see also Saunders and Robinson, this issue).

4.1. 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 after passive waiting or after the emission of an operant response, and (iv) the reward itself. Each of these features can affect the magnitude of the striatal response and whether it is observed primarily within the ventral or dorsal striatum (O’Doherty et al., 2004; Knutson and Cooper, 2005). The focus of the present review is on how the magnitude of these striatal responses is influenced by individual and group differences.

In addition to monetary reward, healthy human subjects have been reported to show striatal activations following exposure to cues associated with food (Small et al., 2001; Beaver et al., 2006; Hommer et al., in press; Demos et al., 2012; Tang et al., 2012), sex (Hamann et al., 2004; Cloutier et al., 2008; Demos et al., 2012), and alcohol (Seo et al., 2011)⁴. There is evidence that these fMRI measured cerebral blood flow (CBF) responses may have been accompanied by an increase in DA release (Box 1). For example, striatal DA release measured in healthy subjects by positron emission tomography (PET) can correlate with fMRI measured activations (Schott et al., 2008). More importantly, evidence of DA release has been observed in healthy human subjects playing video games (Koepp et al., 1998) and following exposure to cues previously paired with monetary reward (Zald et al., 2004; Schott et al., 2008; Martin-Soelch et al., 2011; cf, Hakyemez et al., 2008), food (Volkow et al., 2002; Small et al., 2003), alcohol (Yoder et al., 2009) and amphetamine (Boileau et al., 2007).

The magnitude of the cue-induced DA response might vary with the expected certainty that a reward will be obtained. For example, in nonhuman primates, the largest increases in reward cue-induced DA cell firing are seen under conditions of maximal uncertainty (Fiorillo et al., 2003). Recent evidence raises the possibility that this effect of uncertainty can occur in humans as well: patients with Parkinson’s disease exhibit a larger placebo-induced DA response if they are informed that the chance of receiving L-DOPA medication is 75% as compared to 100% (Lidstone et al., 2010)⁵.

4.2. Effects of cues + drugs

As seen in laboratory animals, there is evidence for reciprocal interactions between drugs and reward related cues with each modulating the response to the other. In healthy human subjects, this has been observed most clearly in two studies where the dopaminergic effects of methylphenidate were augmented by the presence of salient appetitive cues (Volkow et al., 2002, 2004). In the first study, conducted in healthy food-deprived subjects (16–20 h abstinent), the combination of a low dose of methylphenidate (20 mg, p.o.) and food cues (visual, olfactory, taste) elicited greater striatal DA release and greater self-reported hunger than either alone (Volkow et al., 2002). Individual differences in DA release correlated with self-reported hunger and desire for food. In the second study, methylphenidate (20 mg, p.o.) elicited measureable striatal DA release only when it was paired with a salient mathematics task in which subjects could earn a monetary reward. The greater the DA release, the more interesting subjects reported the task to be (Volkow et al., 2004).

A third study provided the first explicit test of whether repeated drug administration could lead to DA sensitization in humans (Fig. 1). Healthy subjects were exposed to three doses of d-amphetamine (0.3 mg/kg, p.o.) on an every other day schedule. Following a two-week break, a fourth dose was given. The DA response to this fourth dose was significantly greater than that elicited by the first dose. A fifth dose, given a full year later, yielded an even larger effect (Boileau et al., 2006). Notably, all doses of d-amphetamine were administered in the same environment (the PET apparatus), rendering the results obtained consistent with environment-specific sensitization. While this study did not determine whether DA sensitization could also have been expressed if the amphetamine had been administered elsewhere, two recent studies conducted in non-dependent stimulant drug users are consistent with the proposal that the presence versus absence of drug associated stimuli can indeed influence the magnitude of drug-induced DA responses. In the first study, individual differences in cocaine-induced increases in extracellular DA were predicted by lifetime histories of stimulant drug use on the street: the greater the past drug use, the greater the DA response (Cox et al., 2009). In this study, participants prepared, manipulated, and self-administered the drug in their usual fashion. That is, cocaine associated cues were clearly present and engaged with. By comparison, in a second very similar study, healthy, non-dependent stimulant drug users were administered a disguised dose of d-amphetamine. In this case, individual differences in DA release were negatively correlated with drug use: the greater the past drug use, the smaller the DA response (Casey et al., 2012). Since similar effects have been well characterized in studies conducted in laboratory animals (Anagnostaras and Robinson, 1996; Anagnostaras et al., 2002; Stewart and Vezina, 1988, 1991; Vezina and Leyton, 2009), a tempting though speculative interpretation of these findings is that the presence versus absence of discrete and contextual drug associated cues modulated the response to the unconditioned drug stimulus. Thus, the presence of salient reward related cues might enable enhanced dopaminergic responding to a pharmacological challenge; the absence of such cues might prevent the expression of enhanced DA responses.

  

Fig. 1

Amphetamine-induced DA sensitization in humans. Healthy male subjects received five doses of d-amphetamine (0.3 mg/kg, p.o.) while laying in a PET scanner. The first three doses were administered every second day. The fourth dose was given following a …

4.3. Age related differences: implications for development

An emerging literature is drawing attention to differences in striatal responding to reward related stimuli in adolescents (13–15 years of age) relative to young adults (early 20s). For example, adolescents have been reported to exhibit larger striatal activation than adults when presented with a stimulus that signals the opportunity to respond for money (Geier et al., 2010) and in response to receipt of the reward (Ernst et al., 2005; Galvan et al., 2006). Moreover, among the adolescents, the greater the striatal response to these cues, the higher their sensation seeking personality trait scores and self-reported excitement (Bjork et al., 2008a)⁶. These age-related responses have been proposed to account for developmental differences in risk-taking and reward-seeking behaviors (Spear, 2011; Ernst and Fudge, 2009; Somerville et al., 2010). Indeed, there is evidence that these striatal effects have predictive validity. For example, among healthy undergraduates (n = 58), the larger the nucleus accumbens response to food cues, the more weight subjects gained at follow-up six months later; the larger the response to sex cues, the greater the amount of sexual activity (Demos et al., 2012).

5.1. Effects of cues

A small literature describes responses to rewards and reward related cues in subjects at risk for substance use disorders (see Tables 2 and ​and3).3). For example, compared to healthy low risk controls, larger striatal responses have been observed in subjects at familial risk for alcoholism when performing the Iowa Gambling Task (Acheson et al., 2009) and following exposure to alcohol odors (Kareken et al., 2004; Oberlin et al., 2012). In comparison, in studies where unfamiliar or otherwise neutral monetary reward cues were presented, high-risk populations exhibit smaller striatal responses than healthy controls (Andrews et al., 2011; Schneider et al., 2012; Yau et al., 2012).

  

Table 2

fMRI BOLD striatal activations observed in human subjects in the presence and absence of reward associated cues. Subjects were individuals with susceptibilities to, or with current addiction disorders.

  

Table 3

PET [¹¹C]raclopride striatal responses observed in human subjects in the presence and absence of reward associated cues. Subjects were individuals with susceptibilities to, or with current addiction disorders.

5.2. Effects of cues + drugs

There is evidence that the effects of drugs and drug associated cues can interact in subjects at risk for addictions. In non-dependent heavy drinking cigarette chippers, for example, alcohol ingestion was found to increase the striatal response to cigarette cues (King et al., 2010). Conversely, there is evidence that cues can augment the effects of drugs. In subjects at elevated risk for addictions, striatal DA responses were augmented relative to low-risk subjects when the substance was ingested in the usual fashion (Setiawan et al., 2010) but diminished when the drug was administered in the absence of drug related cues (Casey et al., 2012). The blunted response reflected both a familial trait and an effect of past drug use: the greater the lifetime history of drug use, the smaller the DA response (Casey et al., 2012). The effects of familial trait and past drug use were independent. This was demonstrated in two ways. First, a control group was included consisting of stimulant drug using subjects matched on substance use to the high-risk subjects but lacking a family history of drug use problems. The high risk subjects with a family history of substance use disorders exhibited lower DA release than either this “low risk” drug using group or stimulant drug naïve subjects. Second, including drug use histories as a potential confounding variable in the statistical analyses did not diminish the contribution of family history. That is, both family and drug use histories produced the same effect but acted as independent contributors.

6.1. 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 et al., 2010; Ihssen et al., 2011): the greater the striatal response, the greater the cue-induced attentional biases (Vollstädt-Klein et al., 2011) and the more severe the obsessive-compulsive drinking symptoms (Vollstädt-Klein et al., 2010). Similarly, in a large study of 326 heavy drinkers, the greater the alcohol cue-induced striatal activation, the greater the severity of alcohol use problems (Claus et al., 2011)⁷.

There is evidence that the above striatal activations may have been accompanied by an increase in DA release. Changes in PET tracer binding values indicative of striatal DA release have been observed following exposure to cues associated with cocaine (Volkow et al., 2006; Wong et al., 2006; Fotros et al., 2012) and heroin (Zijlstra et al., 2008). The greater the cue-induced DA release, the greater the craving (Volkow et al., 2006; Wong et al., 2006; Zijlstra et al., 2008; Fotros et al., 2012).

As seen in other populations, there is also evidence in those with substance use disorders that striatal activations are blunted rather than augmented when addiction related cues are absent. Compared to control subjects, blunted striatal activations occur in response to pictures of food in alcoholics (Ihssen et al., 2011) and to unfamiliar or otherwise neutral monetary reward cues in smokers (Peters et al., 2011) and detoxified alcoholics (Wrase et al., 2007; Beck et al., 2009; cf Bjork et al., 2008b).

6.2. Effects of cues + drugs

In subjects with substance use disorders, stimulant drug-induced striatal DA responses have been reported to be markedly reduced when compared to those observed in healthy controls (Volkow et al., 1997, 2007; Martinez et al., 2005, 2007, 2011, 2012; Wang et al., 2012; Thompson et al., in press; cf Urban et al., 2012; see Tables 2 and ​and3).3). These reductions may possibly aggravate the clinical picture. The lower the DA response, the greater the stimulant drug self-administration observed in separate sessions where the drug and its associated cues were made available (Martinez et al., 2007) and the worse the clinical outcome at follow-up (Martinez et al., 2011; Wang et al., 2012).

Notably, however, in all of the above studies, DA release was measured in the absence of drug cues. This raises the possibility that, even in late stage addiction, the reduced DA responses observed reflect, at least in part, either the absence of drug associated stimuli necessary to enable the expression of enhanced dopaminergic responding or the presence of drug unpaired stimuli capable of inhibiting this response (Vezina and Leyton, 2009). We are aware of only one study that has tested this hypothesis explicitly. In this study, cocaine dependent subjects were administered amphetamine on test sessions with or without drug cues present (videos of actors simulating drug use). Compared to the test session conducted without drug cues, the presence of drug cues actually diminished the DA response further (Volkow et al., 2008), an effect opposite in direction to what had been predicted by the authors. This observation nonetheless adds to the evidence that environmental cues can modulate the pharmacological effects of a stimulant drug challenge. Moreover, as the authors noted, since the cues did not genuinely predict that drug would become available, there may have been a reward prediction error associated with diminished DA release (Schultz et al., 1997; Yoder et al., 2009). This interpretation, though, remains speculative until more studies explicitly testing the proposition are reported. Other factors that might lead to decreased drug-evoked DA release in substance dependent populations include neurotoxic effects of extensive drug use (Little et al., 2003, 2009) and pre-existing risk traits (Casey et al., 2012). Methodological limitations may also be relevant. As noted by Narendran and Martinez (2008), reduced dopaminergic responding could also reflect decreases in D2 or D3 DA receptor affinity, decreases in the ratio of D3 to D2 DA receptors, or an increase in resting baseline DA levels. Preliminary attempts to address some of these possibilities, though, suggest that stimulant drug addicts, tested under the same conditions as in the above studies, have lower rather than higher resting levels of DA (Martinez et al., 2009) and higher rather than lower D3 DA receptor levels at least in D3 DA receptor rich brain regions such as the midbrain and globus pallidus (Boileau et al., 2012).

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.

¹Stimuli associated with opiates and ethanol yield a more complex mix of drug-like and drug-opposite effects (Wikler, 1973; Eikelboom and Stewart, 1982; Stewart et al., 1984; O’Brien et al., 1998; Stewart, 2004). For discussions of how deficit states can augment incentive motivational states and the salience of appetitive cues, see Toates (1986), Hutcheson et al. (2001), and Berridge (2012). A role for dysphoric states in the maintenance of stimulant use has also been proposed in opponent process views of drug taking (Koob and Le Moal, 1997). These states are usually observed soon after prolonged and continuous exposure to drugs but their subsequent elicitation by conditioned cues has also been proposed to contribute to relapse (Siegel, 1979).

²Pharmacological tolerance refers to a decrease in a drug’s potency or efficacy (i.e., maximal effect) with repeated exposure. Conversely, sensitization, also labeled reverse-tolerance, refers to an increase in drug potency or efficacy (sometimes indicated as a significant response to a previously ineffective dose). Both terms describe empirical observations; in and of themselves they do not connote mechanism.

³Despite the different time courses for tolerance and sensitization, there can be temporal overlap since each of these adaptations can occur simultaneously in different systems, as in, for example, those regulating respiration versus those mediating incentive motivation.

⁴Striatal activations can also occur following monetary losses (Kühn et al., 2011). In this study, participants were 154 14-year old video gamers. Frequent gamers (>9 h/week) exhibited a larger striatal response to monetary loss as measured by functional magnetic resonance imaging (fMRI) compared to less frequent gamers. Of note, stimuli indicative of loss are highly salient for gamers. Among professional gamers, greater striatal activation also predicts faster moves, an effect possibly reflecting an enhanced ability of cues to engage approach mechanisms (Wan et al., 2011).

⁵These conditions of uncertain reward delivery simulate a core aspect of gambling. Moreover, in rodents, uncertain reward delivery can increase a cue’s motivational potency (Robinson and Berridge, 2012) and lead to behavioral sensitization to an amphetamine challenge (Singer et al., 2012).

⁶There are also conditions when lower striatal responses are observed, although the results reported thus far are complex and the relevant determining factors remain unclear. For example, lower striatal responses have been observed in adolescents versus adults evaluating a cue prior to being able to respond to it (Geier et al., 2010). Similarly, while adolescents show larger responses than adults to rewards (Ernst et al., 2005; Galvan et al., 2006), the gain in striatal response between large versus small rewards ($5 versus 20 cents) has been reported to be less (Bjork et al., 2004). One interpretation is that adolescents exhibit larger striatal responses to rewards and reward paired cues but smaller responses to more distal cues requiring more elaborate evaluative processes.

⁷A recent case study illustrates how increases and decreases in striatal activity can co-vary with drug-seeking behavior and addiction. A severely alcoholic patient received sessions of transcranial magnetic stimulation (TMS) of the dorsal anterior cingulate cortex. Regional brain activity and self-reported craving were measured simultaneously. As expected, alcohol cue-induced craving was associated with increased activity in the nucleus accumbens. Strikingly, TMS decreased both the craving and the cue-induced activation of the nucleus accumbens, effects that were maintained for three months (De Ridder et al., 2011).

⁸Binge eating disorders share various common features with substance use disorders and pathological gambling. Dysregulated reward seeking, disturbed impulse-control, and various other addictions are commonly co-morbid. Obesity also has been proposed to be a form of behavioral addiction, although this idea is more controversial. For a discussion of these issues, see Ziauddeen et al. (2012).

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