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Decision Making, Affect, and LearningAttention and Performance XXIII$

Mauricio R. Delgado, Elizabeth A. Phelps, and Trevor W. Robbins

Print publication date: 2011

Print ISBN-13: 9780199600434

Published to Oxford Scholarship Online: May 2011

DOI: 10.1093/acprof:oso/9780199600434.001.0001

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Abnormalities in monetary and other non-drug reward processing in drug addiction

Abnormalities in monetary and other non-drug reward processing in drug addiction

(p.445) Chapter 21 Abnormalities in monetary and other non-drug reward processing in drug addiction
Decision Making, Affect, and Learning

Rita Z. Goldstein

Oxford University Press

Abstract and Keywords

Adaptations of the reward circuit to intermittent and chronic supraphysiological stimulation by drugs increase reward thresholds. As a consequence, response to non-drug reinforcers in individuals with chronic drug use or addiction, may be decreased. Clinical symptoms include anhedonia and compulsive drug use, at the expense of the attainment of other rewarding experiences and despite detrimental consequences to the individual's functioning. While most addiction studies focus on the increased valuation of drug reward and drug-related cues, this chapter instead reviews the behavioural and neurobiological evidence for decreased valuation of non-drug reinforcers and cues. Future research should directly address the following question: is processing of drug reward enhanced at the expense of non drug-related reward (at least in certain subgroups of addicted individuals)? Or are these two processes independent?

Keywords:   reward, drug addicts, valuation, non-drug reinforcers, anhedonia, drug use

21.1 The phenomenology and neurobiology of drug addiction

Addiction is a chronic disease characterized by repeated periods of drug craving, intoxication, bingeing, and withdrawal (American Psychiatric Association, 1994). This cycle culminates in the escalated preoccupation with the attainment and consumption of the substance. In particular, the compulsive consumption of the drug occurs at the expense of the attainment of other rewarding experiences and despite detrimental consequences (p.446) to the individual’s functioning (encompassing physical health and other personal, social, and occupational goals). This pattern continues despite attempts of the addicted individual to stop or curtail drug use and even when the rewarding experiences from the drug are markedly reduced (Goldstein and Volkow, 2002).

Animal and human studies show that drugs of abuse exert their reinforcing and addictive effects by activating, and ultimately co-opting, the brain’s reward system, a phylogenetically ancient circuitry normally involved in the reward sensations that are essential to learning and survival. The hub of this system consists of the mesolimbic and mesocortical dopamine (DA) fibers, which originate in the ventral tegmental area and terminate in the ventral striatum (VStr, which encompasses the nucleus accumbens), ventral pallidum, amygdala, hippocampus, and prefrontal cortex (PFC). This circuit’s drug-induced stimulation occurs directly by triggering DA action or indirectly, by modulating other neurotransmitters (e.g., glutamate, gamma aminobutyric acid, endogenous opioids, acetylcholine, cannabinoids, and serotonin). Specifically, all addictive substances increase DA in the mesolimbic brain regions (Volkow et al., 1997a) as directly associated with the reinforcing effects (self-reports of “high”, “rush,” and “euphoria”) of the drugs (cocaine, methylphenidate, and amphetamine) (Laruelle et al., 1995; Volkow et al., 2002a). This is different from non-drug primary (“natural”) reinforcers for which increases in DA appear to occur mostly for reward prediction rather than to the reward itself (Koob and Bloom, 1988; Pontieri et al., 1996, 1998; Schultz et al., 2000). Furthermore, natural reinforcers induce DA increases within the physiological range that habituate with repeated consumption or decrease with satiety. In contrast, drugs of abuse induce supraphysiological DA increases that do not habituate (Bassareo et al., 2002) and that encode for motivation to procure the drug irrespective of whether the drug is pleasurable or not (McClure et al., 2003). Thus, these DA responses imply that drugs are reinforcing not just because they are pleasurable, but because by increasing DA they are being processed as salient stimuli that will inherently motivate further procurement of more drug (regardless of whether the drug is consciously perceived as pleasurable or not) and will facilitate conditioned learning (Volkow et al., 2004a).

With chronic use, striatal DA D2 receptor availability is reduced (Nader and Czoty, 2005; Nader et al., 2006; Volkow et al., 1990, 1997a) as associated with altered function in dopaminergically innervated corticolimbic areas (encompassing the orbitofrontal cortex and anterior cingulate cortex) that mediate processing of reward salience and motivation (McClure et al., 2004b; Wolfram Schultz, 2006; Volkow et al., 1993). Given these long-lasting decreases in DA function, it has been proposed that addicted individuals may take the drug to compensate for the decreased stimulation of DA-regulated reward pathways by non-drug rewards (Volkow et al., 2004a). Indeed, enhanced processing of drug reward and drug-related cues has been frequently studied (Childress et al., 1999; Di Chiara and Imperato, 1988). However, it is still not clear whether this enhanced drug-reward processing is achieved at the expense of non-drug-reward processing in drug-addicted individuals or whether these are independent processes. Several theoretical accounts, mostly based on animal evidence, have been proposed to resolve this issue.

(p.447) 21.2 An underlying change in the value of reward in drug addiction: theoretical accounts

The reward-deficiency syndrome hypothesis posits that individuals prone to addiction have a deficit in recruiting DA motivational circuitry by non-drug rewards, such that abused drugs are uniquely able to normalize DA levels in the VStr to readily motivate drug-taking behavior (Blum et al., 2000). The allostatic hypothesis suggests a chronic deviation of the brain’s reward “set-point” after repeated prolonged exposure to drugs of abuse, which are powerfully reinforcing owing to their potent ability to activate the brain’s reward system. Specifically, it is proposed that the brain reward thresholds become chronically elevated and do not appear to return to baseline levels with abstinence (Koob and Le Moal, 1997). The incentive motivation model posits that, with repeated drug use, cues associated with drug-taking acquire incentive value through sensitization of the brain’s reward system. As the number of paired cue-drug presentations increases, the incentive value of these cues intensifies, making them increasingly “wanted.” With ongoing use, drug cue incentive salience becomes excessive, “wanting” transforms into drug craving, and drug cues become potent perpetuators of further excessive drug taking, despite awareness of associated adverse consequences (Robinson and Berridge, 1993, 2001, 2003). Similarly, a core symptom of our impaired response inhibition and salience attribution (I-RISA) model was postulated to encompass a disproportionate salience, or value, attribution to the drug of choice with a concomitant decrease in the value attributed to other primary and secondary reinforcers by drug-addicted individuals, together enhancing motivation to procure drugs at the expense of the drive to attain most other non-drug-related goals (Goldstein and Volkow, 2002).

Consistent with these models, animal research suggests that, after chronic drug administration, the value of a drug reward is increased (Ahmed and Koob, 1998; Ahmed et al., 2002), while that of a non-drug reward is decreased (Grigson and Twining, 2002). Similarly, human cocaine-addicted subjects, but not controls, showed reduced activation of corticolimbic brain areas when viewing an erotic (non-drug) video, than when exposed to a cocaine video (Garavan et al., 2000). In contrast, other human studies show blunted subjective responses to drug rewards (intravenous methylphenidate), suggesting reductions in the subjective value of drug reward in addicted individuals (Volkow et al., 1997b). Yet a third possibility is that of a generally drug-sensitized brain-reward circuit, where heightened drug motivation may “spillover” to non-drug rewards (Robinson and Berridge, 2003). Here, evidence from animal studies suggests that drug sensitization can increase the incentive value of other rewards, such as sucrose or other foods, a sexually receptive female (for male rats), and conditioned stimuli for such rewards (Fiorino and Phillips, 1999a, 1999b; Nocjar and Panksepp, 2002; Taylor and Horger, 1999; Wyvell and Berridge, 2001). Similarly, in human-addicted individuals, evidence suggests that some cocaine-addicted individuals are hypersexual (Washton and Stone-Washton, 1993) and some substance-dependent individuals may be hyper-responsive to money rewards (Bechara et al., 2002). To resolve these discrepancies, studies could target certain subgroups within addicted individuals, such that heterogeneity in the addicted population (p.448) vis-à-vis sensitivity to reward is explicitly addressed. One such subgrouping could be based on recency of drug use that is associated with enhanced anhedonia but better cognitive functioning (Woicik et al., 2008) and prefrontal drug cue-reactivity (Wilson et al., 2004) in currently addicted individuals. Studies could also dissociate the subjective value of an expected reward (before reward is received) from reward perception at consumption (when reward is received/experienced). Other important dissociations have been suggested by the incentive motivation theory. Here, it is hypothesized that “wanting” drugs (e.g., how much an animal will work to acquire a drug) increases to pathological levels without a parallel increase in drug’s hedonic properties or its “liking” (Robinson and Berridge, 1993, 2001, 2003). This specific hypersensitivity (i.e., sensitization) to the incentive motivational (i.e., “wanting” but not “liking”) effects of drugs (and drug-related stimuli) is hypothesized to ultimately lead to increasingly compulsive patterns of drug-seeking and drug-taking behavior. Clearly, more experimental designs directly examining the value attributed to drug rewards specifically, as it compares with the value attributed to primary non-drug rewards, are needed to further the study of drug addiction.

21.3 Enhanced processing of drug cues at the expense of non-drug cues in human drug addiction?

In this section we review the behavioral evidence suggesting enhanced processing of drug vs. non-drug reward in human drug addiction.

21.3.1 Subjective reports

An impressive body of research has documented the subjective overpowering effects of drugs of abuse (Fox et al., 2005; Gawin, 1991; Lasagna et al., 1955; Leyton et al., 2005; Von Felsinger et al., 1955), suggesting that conditioned drug-related responses trigger an intense desire for the drug, possibly exceeding desire for all other non-drug reinforcers (Volkow et al., 2006b). We have recently developed a brief self-report measure (sensitivity to reinforcement of addictive and other primary rewards, STRAP-R) that dissociates “liking” from “wanting” of expected “drug” rewards as compared to “food” and “sex” while respondents report about three different situations (“current” lab situation, and hypothetical “in general,” and “under drug influence”) (Goldstein et al., 2008a). Results in 20 cocaine-addicted individuals revealed that the reinforcers’ relative subjective value changed when reporting about the drug-related context (“under drug influence:” drug〉food; otherwise: drug〈food). This relative paling of other rewards in the environment was highest in the addicted individuals with the youngest age of cocaine-use onset, suggesting this subjective value shift may represent a cumulative (and not acute) effect of drug use or it may predispose individuals to more intense early drug experimentation and subsequent development of drug addiction.

21.3.2 Objective choice behavior

Although essential, because uniquely human, self-reports are limited due to their potential modulation by extraneous factors encompassing demand characteristics (and social (p.449) desirability), as well as imperfect awareness of one’s own mental processes, which may be all the more pronounced in drug addiction (Goldstein et al., in press). To overcome this limitation, experimental paradigms have directly tested choice behavior. Here, juxtaposing choice for drug against choice for competing reinforcers, studies have shown that previously drug-exposed animals choose cocaine over novelty (Reichel and Bevins, 2008), adequate maternal behavior (Mattson et al., 2001), and even food, a primary reinforcer needed for survival (Aigner and Balster, 1978; Woolverton and Anderson, 2006; Zombeck et al., 2008). Parallel human studies use the multiple-choice procedure that provides an index of the relative reinforcing value of a drug vs. alternative reinforcers (Griffiths et al., 1993, 1996). Here, studies show that drug-addicted individuals routinely choose their drug of choice over money (Donny et al., 2003; Hart et al., 2000; Martinez et al., 2007b). This effect is modulated by drug dose, as recently demonstrated: choice for immediate alcohol (vs. 1-week delayed monetary delivery) increased with alcohol dose (12, 24, or 36 ounces) in 27 young binge-drinkers (〉5 drinks at one sitting twice a week) (Benson et al., 2009). Interestingly, at the highest alcohol dose, alcohol choice was enhanced even in the immediate monetary payment condition (Benson et al., 2009). This is important because, compared to controls, drug-addicted individuals show preference for immediate over delayed reward as associated with risky or disadvantageous decision making (reviewed below in S21.6). Whether such preference for immediate reward may be biased in the context of, and towards, the drug of choice (and away from other non drug rewards), remains to be tested.

We developed a picture-choice task to provide an opportunity for testing choice for drug-related, as compared to competing, reinforcers (pleasant and unpleasant pictures) outside of an acute drug-administration paradigm, therefore suitable for use even when direct drug administration is not feasible or ethical (e.g., in abstaining or treatment-seeking drug-addicted individuals) (Moeller et al., 2009). Results showed that 20 cocaine-addicted individuals selected more, and worked more for, cocaine pictures than matched healthy control subjects. Results also revealed modulation of the drug-picture choice by the alternative pictures, such that the drug-picture choice was equivalent to pleasant-picture choice but enhanced when compared to unpleasant-picture choice, possibly indicative of modulation of actual drug choice by other pleasant or aversive stimuli in drug-addicted individuals as consistent with both human and animal studies (Ahmed and Koob, 1997; Brown and Erb, 2007; Christensen et al., 2008; Higgins et al., 2004; Lenoir et al., 2007; Sinha et al., 2000, 2006; Stairs et al., 2006). Importantly, higher choice for viewing cocaine pictures, even when directly compared to selections of the other positively valued and reportedly more pleasant pictures, correlated with higher frequency of actual cocaine use (as possibly indicative of higher drug-addiction severity). It is, therefore, possible that such choice behavior would be differently expressed depending on an individual’s phase within the addiction cycle (e.g., intoxication, craving, bingeing, withdrawal) and consequently remains to be studied longitudinally and in various subgroups within the heterogeneous-addicted population (e.g., those who are positive vs. negative for cocaine in urine, an objective measure of recency and frequency of use). Overall, such disadvantageously enhanced drug choice could provide a marker of the neurocognitive dysfunction that characterizes drug addiction.

(p.450) 21.3.3 Cognitive processes

Cognitive studies similarly demonstrate that drug-related cues elicit a unique pattern of reactions in drug-addicted individuals. For instance, exposure to drug-related stimuli (e.g., pictures, paraphernalia) in drug-addicted individuals impacts classical neuropsychological measures of cognitive interference (e.g., the Stroop effect) (Carter and Tiffany, 1999; Duka and Townshend, 2004; Franken et al., 2000; Hester et al., 2006; Mogg and Bradley, 2002) as indicative of attention bias and automatic cue reactivity. Similarly, tailoring other neuropsychological measures to specifically target drug addiction also shows promising results, e.g., drug-addicted as compared to control subjects name more drug-related words, while there are no group differences on the regular/neutral semantic fluency (naming animals or fruits/vegetables) (Goldstein et al. 2007c). Thereby, one could test the underlying mechanisms which, in addition to attention bias, may also include overlearning of drug-predictive cues (Redish, 2004), “fresher” memory traces of drug effects (Lee et al., 2006), and heightened arousal/autonomic reactions evidenced in addicted individuals in response to drug-related cues (Carter and Tiffany, 1999b; Ehrman et al. 1992; Glautier and Drummond, 1994; Margolin et al., 1994; Sinha et al., 2000). An open question in these studies is whether this bias to drug-related processing decreases efficiency of non-drug related processing, which would be evidenced by a cognitive compromise under a neutral context, as indeed suggested using classical neuropsychological studies in addiction (e.g., Woicik et al., 2008). We speculate that this cognitive compromise in addicted individuals is not fully driven by a neutral (i.e., not motivating) context, and that even under high levels of motivation, compromised neurocognitive functioning could be detected as suggested by results of neuroimaging studies, as reviewed next.

21.4 Neuroimaging studies utilizing monetary reward in drug-addicted individuals

Neuroimaging research has predominantly focused on responses to drug-related stimuli alone and rarely examined how these findings compare with the processing of non-drug reinforcers. We, therefore, next review the neuroimaging studies that used non-drug-related reward in addicted individuals. We start with reviewing the studies that utilized money as a reinforcer. The importance of using monetary reward lies in the conditioning between monetary availability and drug procurement. If processing of this secondary generalizable reinforcer is compromised in addicted individuals, it is possible that, for this population, only more immediate drug-related cues (e.g., pictures or a video; see: Garavan et al., 2000) or the drug itself, could activate this circuit at a comparable level with that induced by a non-drug-related reward in the non-drug-addicted individual. Such evidence would provide support for the possibility that processing of non-drug reward is compromised in drug addiction.

In a functional magnetic resonance imaging (fMRI) study, we examined responses to monetary reward received for correct performance on a sustained attention task in 16 cocaine-addicted (abstinence 1–90 days) as compared to 13 healthy control subjects (p.451) (Goldstein et al., 2007b). Sustained monetary reward was associated with a robust and complex neuronal activation pattern in the comparison subjects (Fig. 21.1): there was a trend for the left orbitofrontal (OFC) to respond in a graded fashion (45¢〉1¢〉0¢), the lateral and medial PFC (including anterior cingulate cortex) responded instead to the two conditions of monetary value equally (45¢ = 1¢〉0¢), while the mesencephalon displayed a third pattern of sensitivity to the highest available reward only (45¢〉1¢ = 0¢). In general, these results were consistent with role of the (a) OFC in relative reward processing in the primate (Tremblay and Schultz, 1999) and in healthy human subjects (Breiter et al., 2001; Elliott et al., 2003; Knutson et al., 2000; Kringelbach et al., 2003; O’Doherty et al., 2001); (b) PFC in the control of attention (Hornak et al., 2004), possibly irrespective of reward magnitude (Watanabe, 1989); and (c) mesencephalon in an all-or-nothing reward processing in the primate (Tobler et al., 2005) and in healthy human subjects (Elliott et al., 2003). The cocaine-addicted subjects did not display this complex pattern of activation to monetary reward, demonstrating either reduced regional fMRI signal in the between-group analyses, or less sensitivity to differences between the monetary conditions in the within-group analyses. A relative exception was the left cerebellum, where only the cocaine abusers displayed a significant monetary effect (45¢〉0¢; note, however, that the between-group analysis still showed larger reward-related activations in the comparison subjects). This within-subjects result is consistent with reports of compensatory mechanisms in the cerebellum in psychopathology, e.g., over-reliance on the cerebellum by cocaine abusers during a working memory task (Hester and Garavan, 2004) and by Parkinson’s patients during a rewarded task (Goerendt et al., 2004). Extending our prior study (Goldstein et al., 2007b), we recently reported that anterior cingulate hypoactivations in cocaine users cannot be attributed to task difficulty or disengagement but that, nevertheless, emotional salience modulates this region’s responses in proportion to drug use severity (Goldstein et al., 2009a).

Interestingly, using a self-report measure adapted from studies in opiate addiction (Martin-Soelch et al., 2001), our results showed that, while most controls reported valuing higher amounts of money more than lower amounts, more than half of the cocaine-addicted individuals rated the value of all monetary amounts equally ($10 = $1000) (Goldstein et al., 2007a) (Fig. 21.2). Eighty-five percent of the variance in this constrained subjective sensitivity to monetary reward gradients in the cocaine abusers was attributed to lateral OFC, amygdala, and medial frontal gyrus responses to monetary reward. This finding may seem perplexing in light of the frequently used delay discounting and gambling reward paradigms, where time and reward contingencies are juxtaposed to examine the effects of the created conflict on decision-making/choice behavior (e.g., Bechara and Damasio, 2002; McClure et al., 2004a). In contrast, in our study, subjects did not choose between smaller immediate vs. larger delayed monetary rewards. Instead, we focused on the individual’s subjective experience (evaluation of a non-drug reward). We interpreted these findings to suggest preserved reward sensitivity (illustrated by the small squares in Fig. 21.3A) that would allow the detection of differences between reinforcers in the healthy control subjects (monotonically positive function). In contrast, the low sensitivity (p.452)

                      Abnormalities in monetary and other non-drug reward processing in drug addiction

Fig. 21.1 Average fMRI signals in the left orbitofrontal cortex (A: OFC), prefrontal cortex (B: PFC, mean signal), right mesencephalon (C: MSN), and left cerebellum (D: CBL) as a function of monetary reward (white = 0¢; gray = 1¢; black = 45¢) and diagnostic group (left: 16 cocaine abusers; right: 12 comparison subjects, ss). Bar graphs represent mean % signal change from baseline ± SEM. ANOVA F results are presented on the right: df = 2, 25 (Money) or 1, 26 (Group). Results of significant t-tests are marked inside the figures: df = 11 (comparison subjects), 15 (cocaine), 26 (group differences); all significant t〉|2.1|; *P〈0.05; **P〈0.01.

Adapted with permission from: Goldstein et al., 2007b; figure #2.

in cocaine abusers (large squares in Fig. 21.3B) would not permit the distinction between stimuli of different gradations but rather allow an all-or-nothing identification only of the stimuli that reach the threshold required for perception of reinforcement (step function). Results of this self-reported data need to be confirmed with more objective measures of behavior, especially given the impairments in self-awareness in addiction, as we recently suggested (Goldstein et al.,in press). It also remains to be determined whether different subgroups within the addicted population (e.g., urine positive vs. negative for the drug) would evidence differential subjective (or more objective) sensitivity to non-drug reward (as indeed suggested by our preliminary results, Fig. 21.2B). (p.453)
                      Abnormalities in monetary and other non-drug reward processing in drug addiction

Fig. 21.2 Money value rating scale. A: Subjective ratings in control subjects (N = 13, white) compared with cocaine abusers (N = 16, black). B: Data presented for two cocaine subgroups: subjects with flat ratings on the money rating scale (N = 9, black squares) vs. subjects with non-flat ratings (N = 7, black triangles). Error bars represent standard error.

Adapted with permission from: (Goldstein et al., 2007a; figure #2.

                      Abnormalities in monetary and other non-drug reward processing in drug addiction

Fig. 21.3 Diagrammatic representation of the changes in relative and absolute reward in addiction. Dotted lines reflect the threshold for a stimulus to be perceived as reinforcing: the threshold is lower in the non-addicted (A) and higher in the drug-addicted (B) individual. Dashed lines reflect the function that describes the perception of a stimulus as subjectively valuable. The high sensitivity to the reinforcers (small squares, A) allows the detection of small reinforcers and differences in magnitude between reinforcers in control subjects (monotonically positive function). The low sensitivity in cocaine abusers (large squares, B) does not permit the distinction between stimuli of different gradations but rather identify only those that reach the threshold required for the stimulus to be perceived as reinforcing (step function).

With permission from: Goldstein et al., 2007a; figure #4.

Using the same sustained-attention task and monetary reward quantities (45¢, 1¢ and 0¢), while recording event-related potentials (ERPs), we replicated the impact of monetary reward on neural responses (measured here with the P300 ERP component) in healthy young adults (Goldstein et al., 2006). This result was consistent with a large body (p.454) of literature implicating the P300 in processing reward magnitude and valence (e.g., Yeung and Sanfey, 2004). Importantly, we subsequently replicated these results in 18 healthy individuals matched on age and other demographic factors to cocaine-addicted individuals (abstinence 0–4 days) (Goldstein et al., 2008b): while in the control subjects the amplitude of the P300 component was higher in the 45¢ condition than the 0¢ condition, a similar P300 response to money was not significant in the cocaine-addicted subjects. In parallel, only the control subjects reacted faster to the highest monetary condition (45¢) as compared to the neutral cue (0¢). Importantly, only in the control subjects, these P300 amplitude differentials directly intercorrelated with the respective behavioral adjustments to the monetary incentive (45¢〉0¢ with accuracy and 1¢〉0¢ with reaction time); in the cocaine-addicted subjects, the better the accuracy adjustment for the high monetary condition, the less frequent the cocaine use during the year preceding the study. Our most recent results suggest that such compromised P300 responses to money characterize both cocaine urine positive and cocaine urine negative currently addicted individuals (unpublished observation).

Overall, reduced sensitivity to non-drug reward (as objectively measured with fMRI and ERPs) may represent an additional symptom of the reward threshold elevations and reward sensitivity decreases characterizing chronic drug use (Ahmed and Koob, 1998; Ahmed et al., 2002), hypothesized to result from adaptations of the reward circuit to intermittent and chronic supraphysiological stimulation by drugs (Volkow and Fowler, 2000).

21.4.1 Neuroimaging studies focusing on the ventral striatum

Note that in our fMRI study, the VStr (or dorsal striatum) was not activated to money (Goldstein et al., 2007b), which could be attributed to technical factors (e.g., statistical threshold, signal loss) or the lack of incorporation into the task design of an anticipatory phase (reward contingencies were constant and predictable). Other fMRI studies of monetary reward anticipation showed the expected VStr activations in healthy control subjects (e.g., Knutson et al., 2005). Utilizing this same monetary incentive delay task, authors recently showed that, while the VStr was activated to both gain and loss (gain〉loss) in healthy control subjects, these activations were significantly higher than in abstinent alcoholics (recruited from an inpatient detoxification treatment program, abstinence 5–37 days) (Wrase et al., 2007). Interestingly, the alcoholics with the highest VStr monetary gain activations had the lowest self-reported alcohol craving. Importantly, alcohol (vs. neutral) pictures elicited significant right VStr activation in the alcoholics and the higher this activation, the more the alcohol craving (Wrase et al., 2007). Consistent with the premise of the current review, the authors interpreted these findings to reflect the selective diversion of motivational resources away from conventional rewards and toward drug rewards in addicted individuals (these findings were not interpreted to reflect a global deficit of brain activation in alcoholics, e.g., due to hypoperfusion, or a selective blunting of the VStr). Although the direct comparison between the different classes of reinforcers (money vs. drug cues) remains to be accomplished, this study offers strong support for the hypothesis that the value of drug-related cues overpowers that of (p.455) non-drug-related cues in addicted individuals. In a similar vein, we recently reported that even abstract cues, such as drug words (but not neutral words), activated the mesencephalon (the main source of dopamine release and projection to the VStr) in cocaine users but not demographically matched healthy control subjects; these increased drug-related mesencephalic responses were associated with enhanced verbal fluency specifically for drug (but not neutral) words in the addicted subjects (Goldstein et al., 2009b).

Opposite evidence has also been suggested. Here, a modified version of the monetary incentive delay fMRI task was used in 23 controls and 23 abstinent treatment-seeking alcoholics (scanned 6–26 days after abstinence) (Bjork et al., 2008b). While there were no differences between the groups during the anticipatory phase, the VStr (and insula and anterior cingulate cortex) showed higher responses in the alcoholics than controls to reward delivery ($5.0 or $.5) vs. no reward ($0.0); these regions were also deactivated by reward-outcome deferrals (i.e., frustration) in the alcoholics more than in the controls. The authors interpreted these results as indicative of a physiological signature of reward-centric bias in addiction, and of motivational and emotional instability/impulsivity/greater urgency to alleviate negative emotions (Bjork et al., 2008b). Because this task has been designed to emphasize the anticipatory and not consummatory phase, and given some inconsistencies in this study (e.g., although there were significant reaction time responses to reward in controls but not alcoholics, the controls did not show VStr responses to reward during the reward delivery phase), these results await replication and validation in other populations of addicted individuals. Of note here are also previous positron emission tomography (PET) studies that measured regional cerebral blood flow during processing of monetary reward in addicted (e.g., smokers, opiate users) and non-addicted individuals (Martin-Soelch et al., 2001, 2003); here too conclusive statements should be deferred due to lack of direct comparisons between the study groups.

21.5 Other non-monetary reward

Studies of neural responses to drug-related vs. non-drug-related cues (including potential reinforcers) in addicted vs. non-addicted individuals have generally utilized electrophysiological recordings, while subjects view drug-related, pleasant, unpleasant, and neutral pictures. Including non-drug emotional stimuli, in addition to the usual drug-related vs. neutral pictures, add to the fledgling emotional neuroscience literature in drug addiction (Aguilar de Arcos et al., 2005; Verdejo-Garcia et al., 2006). For example, we used an ERP component, the LPP, as a psychophysiological measure of automatic (Hajcak et al., 2007) or bottom-up (Ferrari et al., 2008) motivated attention bias elicited by drug-related stimuli in 20 active cocaine-addicted individuals (abstinence 0–14 days), as compared to matched controls (unpublished observation). Preliminary results showed that the LPPs elicited by cocaine pictures were similar to LPPs elicited by the other emotional pictures only in the addicted individuals; in the controls, LPPs elicited by the cocaine pictures were instead comparable to LPPs elicited by the neutral pictures, and both were significantly smaller than LPPs elicited by the other emotional pictures. These findings suggest that, for the cocaine-addicted subjects, but not controls, both cocaine and emotional stimuli (p.456) automatically increase attention. A recent study in active heroin-addicted individuals (24-h abstinence) reported similar drug-related P300 enhancements (Lubman et al., 2009) as correlated with baseline craving (Lubman et al., 2008). The more recent study (Lubman et al., 2009) also showed lack of the typical P300 reward enhancement to pleasant vs. neutral or drug pictures, consistent with inhibited responding to non-drug reinforcers in addicted individuals. Compromised responsiveness to pleasant pictures in heroin-addicted individuals was similarly reported in a recent fMRI study, where the bilateral dorsolateral PFC was activated to pleasant pictures in 18 healthy controls but not in 16 abstinent (1–24 weeks), inpatient, male, heroin addicts (Zijlstra et al., 2009). Interestingly, in initially detoxified alcoholic subjects, VStr and thalamic response to pleasant vs. neutral stimuli predicted drinking days and alcohol intake within a 6-month follow-up period (Heinz et al., 2007). Taken together, the preserved responding to non-drug reinforcers may characterize individuals with less pronounced illness severity or reflect a protective factor in drug-addicted individuals. Indeed, offspring of alcoholics with higher DA D2 receptor availability may be protected against developing alcoholism through more adaptive recruitment of corticolimbic circuits (including the OFC) needed for positive emotion regulation (Volkow et al., 2006a).

A promising line of functional neuroimaging research has been using masked cues to study processing of stimuli outside of conscious awareness. In an event-related fMRI study in 21 cocaine patients, 33 ms “unseen” cocaine (and sexual) cues activated the subcortical reward circuitry (encompassing the VStr/pallidum, amygdala, insula, OFC, as characterized by prior studies in humans: Childress, 2002; McClure et al., 2004b) and in animals (Di Chiara and Imperato, 1988; Koob and Bloom, 1988; Wise, 2005) (Childress et al., 2008). Importantly, the “unseen” cocaine cue-induced ventral pallidum/amygdala activation predicted future positive affect to visible versions of these same cues (in an off-magnet affective-priming task, two days later). This correlation demonstrated the functional significance of the “unseen” cues, consistent with recent reports showing that appetitive signals (e.g., for money: Pessiglione et al., 2007; a tasty juice: McCabe et al., 2009b; or happy faces: Winkielman et al., 2005) outside of conscious attention can influence ongoing (e.g., grip force: Pessiglione et al., 2007) or subsequent (e.g., seat choice: McCabe et al., 2009b; or drinking of a novel beverage: Winkielman et al., 2005) motivated behavior.

21.6 Association with impulsivity in drug addiction

A modified value attributed to rewards in the environment may alter underlying stimulus-reinforcement association learning. This modified response to reinforcement in drug-addicted individuals may in turn contribute to cognitive-behavioral and emotional impairments that take the form of over-valuation or bias towards immediate reward and discounting of delayed rewards (Kirby and Petry, 2004; Monterosso et al., 2007) that together can lead to disadvantageous decision making (Bechara et al., 2002; Bolla et al., 2003) and impulsivity (Bjork et al., 2008a; Moeller et al., 2005). The impact of reward on tasks of decision making and other higher-order executive functions (e.g., set-shifting, (p.457) concept formation, reversal learning) is further reviewed elsewhere in this volume (see Chapter 22).

In our fMRI monetary-reward task, we observed a significant correlation between the dorsolateral PFC response to monetary reward and trait self-reported inhibitory control (measured with Tellegen’s Multidimensional Personality Questionnaire: Tellegen and Waller, 1997) in cocaine-addicted individuals (Fig. 21.4), suggesting that hyposensitivity to reward in the PFC is associated with the reduced self-control (impulsivity) reported by the cocaine abusers (Goldstein et al., 2007b). This result highlighted that the association between the PFC and control of behavior (Miller and Cohen, 2001) may be modulated by the PFC sensitivity to reinforcement. Subcortical regions may also be involved. For example, the higher the mesencephalic (ventral tegmental area/substantia nigra) response to money, the more the self-reported reward-dependence as possibly modulating less impulsivity (measured as exploratory excitability) in healthy individuals (Krebs et al., 2009). In contrast, VStr activation to monetary reward was associated with higher impulsivity, or the objectively measured preference for immediate over delayed rewards (Hariri et al., 2006). It remains to be determined whether these differences pertain to the brain region examined and underlying mechanisms (e.g., DA D2 receptor availability) or the measurement chosen (e.g., self-report vs. objective/behavioral measures of impulsivity).

21.7 Modulating factors

Thus, neural responses to reward seem to differ between addicted individuals and healthy control subjects, and these differences are behaviorally significant. However, the effect of the following factors needs to be considered when interpreting results of these studies; clearly more studies and the identification of additional factors is needed.

21.7.1 Perceived opportunity to consume drugs

A recent study showed attenuated dorsal striatal (caudate) responses to both monetary gains and losses (on a card-guessing task for which subjects could earn $1.00 or lose $.50) in 18 male habitual cigarette smokers, told that they would be able to smoke during the study, as compared to those who anticipated having to wait several hours before having the opportunity to smoke (Wilson et al., 2008). The authors concluded that monetary gains were processed as less rewarding and monetary losses as more punishing by individuals anticipating an opportunity to smoke soon, relative to those expecting a significant delay before having the chance to smoke, as modulated by the negative affect associated with imminent drug use further increasing the desire to engage in drug use (Wilson et al., 2008). This factor needs to be explicitly examined in other drug-addicted populations (e.g., cocaine urine positive vs. negative individuals, current users vs. abstinent or treatment-seeking individuals).

21.7.2 Sex differences

Recent evidence points to other modulating factors, such as hormones or gender. For example, during the midfollicular phase (days 4–8 after onset of menses, when estrogen (p.458)

                      Abnormalities in monetary and other non-drug reward processing in drug addiction

Fig. 21.4 Correlation between the lateral PFC and inhibitory control in 16 cocaine abusers. Scatterplot shows association between the fMRI signal change for monetary reward as compared to the neutral cue (45¢〉0¢) in the lateral PFC with MPQ self-control (r = 0.88, P = 0.001); the inserted statistical map of brain activation depicts the cluster location corresponding to this correlation. Thresholded at P〈0.05 uncorrected. Minimum cluster size 100 contiguous voxels, 2700 mm3.

Adapted with permission from: Goldstein et al., 2007b; figure #3.

is unopposed by progesterone), women anticipating uncertain rewards activated the OFC and amygdala more than during the luteal phase (6–10 days after luteinizing hormone surge) (Dreher et al., 2007). Similar differences (follicular〉luteal phase) were seen during reward delivery in the mesencephalon, striatum, and left fronto-polar cortex. Activity in the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Also, men activated the ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial PFC at time of reward delivery (Dreher et al., 2007).

21.7.3 Age

Signal increases in the right VStr during anticipation of responding for large gains vs. non-gains positively correlated with age and, in a direct comparison, 12 adolescents (12–17 years of age) evidenced less recruitment of the right VStr and extended amygdala compared with 12 young adults (22–28 years) (Bjork et al., 2004). However, another study reported the opposite pattern, where exaggerated magnitude of VStr activity, relative to PFC activity, was observed in 13 adolescents (13–17 years), compared with 12 adults (23–29 years), and 16 children (7–11 years) (Galvan et al., 2006).

21.8 The underlying mechanism for a possible reward value shift in drug addiction

Dopamine is an essential neurotransmitter in processing reward and reward prediction errors (McClure et al., 2004b; Wolfram Schultz, 2006; Volkow et al., 1993) and in salience (p.459) enhancement (Volkow et al., 2002b, 2004b). The abnormalities in reward processing in drug addiction are therefore not surprising and are consistent with similar compromises in other dopaminergically mediated psychopathologies. For example, monetary incentives do not modulate grip force in patients with bilateral striatal-pallidal damage (Schmidt et al., 2008) and Parkinson’s disease patients are less proficient in learning the predictive value of monetary reward cues, displaying diminished functional connectivity of the mesencephalon and VStr (Schott et al., 2007). In healthy individuals, a preliminary pharmacological fMRI study suggested that a dopaminergic agent (0.25 mg/kg oral dopadextroamphetamine vs. placebo) modulated VStr responses during anticipation of gains, such that responses were blunted in peak amplitude but extended in duration (Knutson et al., 2004). However, the association between DA and reward processing is not linear. For example, higher baseline striatal DA synthesis is associated with better reward-learning but worse learning with further dopaminergic intervention (with bromocriptine) in healthy controls; in contrast, lower baseline striatal DA synthesis is associated with better punishment-learning and DA enhancement improves reward learning (Cools et al., 2009). It is, therefore, possible that improving baseline DA function in selected subgroups of drug-addicted individuals may improve their reward processing. In this context, preliminary results in our laboratory showed a direct correlation between baseline DA receptor availability (measured with C11 raclopride and PET), and thalamic and medial PFC response to money (measured with fMRI) in seven cocaine-addicted individuals (Asensio et al., accepted).

More direct evidence for the role of DA in the modified reward valuation in addicted individuals derives from another PET study, where blunted amphetamine-induced DA release in the VStr (and dorsal striatum) was predictive of actual choice for cocaine over money (and not of positive subjective drug effects) in 24 cocaine-addicted individuals (14 days abstinence), as compared to 24 controls (Martinez et al., 2007). These results were all the more compelling as subjects could choose to receive $5 or self-administer smoked cocaine (6 or 12 mg) with street value 〈$5. Although results of this study need to be validated using a more immediate monetary gain (the $5 gain was delayed, given as a merchandise voucher redeemable at local stores and paid upon discharge from the study), choice on this self-administration paradigm may model relapse (drug choice followed a priming dose/drug cue). In fact, the authors interpreted these results to indicate that the cocaine-addicted individuals who are most vulnerable to relapse are those with the lowest presynaptic DA function because their DA levels may be insufficient to provide the signal that could shift habitual behavior (drug choice, lesser reward) to a more advantageous behavior (monetary choice, greater reward).

21.9 Summary and conclusions

We reviewed evidence for a modified valuation of monetary and other non-drug-related reward in drug-addicted individuals. These abnormalities may contribute to the ascribed motivational impairments and deficits in controlling drug-taking behavior in drug-addicted individuals. For example, restricted range of subjective valuation of reward may play a mediating role in the ability to use internal cues and feedback from the environment (p.460) to inhibit inappropriate (drug-escalated) behavior. Moreover, a “flattened” sensitivity to gradients in reward may predispose individuals to disadvantageous decisions (e.g., trading a car for a couple of cocaine hits). Without a relative context, drug use and its intense effects (craving and high) could become all the more overpowering.

21.10 Recommendations

Anhedonia (common during acute and long-term drug withdrawal) and difficulty to replace drug-taking behaviors with other, less harmful, activities are common symptoms in drug addiction. Targeting the neurobiology of reward processing in addiction may be beneficial in devising behavioral and pharmacological intervention strategies to alleviate these symptoms. For example, drug abusers who evidence a compromised sensitivity to non-drug reward could be identified for tailored interventions to improve associated cognitive-emotional skills (e.g., attention, response shifting, learning and memory, general value estimations). Because decreased DA striatal release may be associated with reduced activation in the OFC and anterior cingulate cortex to non-drug reward, and enhanced activation in these same regions in response to drug-related cues as correlated with drug craving (Volkow et al., 2004a), pharmacological enhancement or direct brain stimulation of these dopaminergically innervated corticolimbic brain regions may also be beneficial.

21.11 Future directions

Both positive (vouchers, privileges) and negative (incarceration) reinforcers are used in the management of the drug abuser. Therefore, future research needs to be expanded to include negative reinforcers. A particularly important question to be explored is how reward value could modulate choice behavior such that non-drug rewards would be chosen over drug use in addicted individuals. Here promising new approaches suggest that stimuli in a virtual environment (computer game) can acquire motivational properties that persist and modify behavior in the real world (McCabe et al., 2009).


Time dedicated to working on this chapter was supported by grants from the National Institute on Drug Abuse (1R01DA023579 and R21DA02062).


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