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Hungry to gamble? Ghrelin as a predictor of persistent gambling in the face of loss
Biological Psychology 139 (2018) 115–123
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Biological Psychology journal homepage: www.elsevier.com/locate/biopsycho
Hungry to gamble? Ghrelin as a predictor of persistent gambling in the face of loss Travis Sztainerta, Rebecca Hayb, Michael J.A. Wohla, Alfonso Abizaidb, a b
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Carleton University Department of Psychology, Canada Carleton University Department of Neuroscience, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Ghrelin Feeding Cravings Gambling Addiction Reward Behavior
Ghrelin, a peptide hormone associated with appetite, is also linked to increased reward seeking behaviors, including food, sex, and drug seeking behaviors through the stimulation of the mesolimbic dopaminergic system. Moreover, plasma ghrelin concentrations are increased by cues that predict rewards, suggesting that cues could facilitate cravings and ultimately relapse. In this project we examined the effects of an overnight fast, a manipulation known to increase ghrelin concentrations, on gambling behaviors. We also examined if cues associated with gambling would also increase ghrelin and, if so, we examined if these increases were associated with gambling behavior. One hundred and one (37 females) participants were asked to fast overnight or after breakfast and then asked to complete food and gambling craving questionnaires. Participants were then presented with gambling cues (a casino like environment in the lab) or a control cue (a cubicle with a computer). After the cue, subjects filled gambling craving questionnaires, and were allowed to gamble. Following 25 practice spins, the slot machines were fixed so that all subsequent spins were losses, and the number of spins in spite of losses were quantified. Blood samples were collected throughout the experiment. Results showed that the gambling cues significantly increased ghrelin concentrations particularly in fasted individuals, and that ghrelin concentrations 20 min after the cue were the best predictor for gambling persistence in the face of continued loss (p < 0.05). Our results suggest that cues that predict the opportunity to gamble have an acute effect on ghrelin concentrations that is facilitated by fasting, and that ghrelin concentrations are a significant predictor of gambling persistence.
Gambling is a legal and increasingly socially acceptable activity in most parts of the world (see (Cosgrave & Klassen, 2001). However, a subset of players (1–2% of the population) develop a gambling disorder, which is associated with an array of social, legal and psychological problems (Nautiyal, Okuda, Hen, & Blanco, 2017; Potenza et al., 2013; Potenza, 2014). This is because disordered gamblers spend an excessive amount of money gambling, even in the face of continued loss (LaPlante, Nelson, LaBrie, & Shaffer, 2011; Young, Wohl, Matheson, Baumann, & Anisman, 2008). In general, it is thought that pathways to disordered gambling include the positive valance attributed to successful gambles (i.e., reinforcement) and the engrossing nature of gambling games that helps relieve negative affective (or valance) states (Blaszczynski & Nower, 2002; Young & Wohl, 2009). As a result, despite the negative consequences of continued gambling, many gamblers experience an overwhelming, often irresistible, craving to gamble (Sharpe, 2002). Recent interest in gambling-related cravings has yielded the
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development of several single-item as well as multi-item questionnaires specifically designed to assess the subjective experience of craving gamble. For example, the Gambling Craving Scale (Young & Wohl, 2009) is a valid psychometric tool to assess negative and positive valance dimensions associated with cravings and also associated with the tendency of disordered gamblers to continue gambling despite continuous losses. Although there are several reliable psychometric measures like the GACS that can be used to detect and predict pathological gambling, the relationship between craving, and biological markers or substrates underlying gambling cravings have not been clearly established. The present experiment addressed this gap by examining whether craving to gamble is associated with biological markers associated with risk taking to predict excessive gambling. There is extensive literature in preclinical studies that link cravings in direct association with activity of the mesolimbic dopaminergic system, a neural network that is critical for reward seeking behaviors (positive valence) and that is also active in response to stressors
Corresponding author. E-mail address: [email protected] (A. Abizaid).
https://doi.org/10.1016/j.biopsycho.2018.10.011 Received 23 March 2018; Received in revised form 18 October 2018; Accepted 18 October 2018 Available online 28 October 2018 0301-0511/ © 2018 Elsevier B.V. All rights reserved.
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Fig. 1. Experimental design and casino gambling cues used as an independent variable. Fig. 1A depicts the experimental design used in the current study, where subjects were asked to participate in the experiment soon after they consumed breakfast or following an overnight fast (independent variable 1). After a series or questionnaires and blood samples, subjects were presented with either a gambling cue (the casino environment) or no gambling cues (a desk with a computer; independent variable 2, Fig. 1B). A blood sample was collected 20 min following the presentation of the cue and participants were tested for gambling persistence.
heroin and cocaine self-administration studies (Cabeza de Vaca & Carr, 1998; D’Cunha, Sedki, Macri, Casola, & Shalev, 2013). In correlation with this, food restriction also causes an increase in the secretion of the hormone ghrelin, a signal linked to metabolic status and reward seeking behaviors (Abizaid, 2009; Edwards & Abizaid, 2016). Receptors for ghrelin are detected in several hypothalamic and extra hypothalamic regions important for feeding and for reward seeking behaviors including the VTA (Guan et al., 1997; Mani et al., 2014; Zigman, Jones, Lee, Saper, & Elmquist, 2006). Ghrelin acts on these regions to promote reward seeking behaviors (King, Isaacs, O’Farrell, & Abizaid, 2011; Wellman, Davis, & Nation, 2005, 2011; Wellman et al., 2012; Wellman, Clifford, & Rodriguez, 2013), whereas ghrelin receptor antagonists or mutations to the ghrelin receptor lead to reduced reward seeking behaviors(Chuang et al., 2011; Jerlhag & Engel, 2011; Jerlhag, Egecioglu, Dickson, & Engel, 2010; Jerlhag, Landgren, Egecioglu, Dickson, & Engel, 2011; Perello & Zigman, 2012; Salome et al., 2009; Skibicka, Hansson, Egecioglu, & Dickson, 2012; St-Onge, Watts, & Abizaid, 2016; Suchankova, Steensland, Fredriksson, Engel, & Jerlhag, 2013; Verhagen et al., 2011). Thus, just like food restriction, exogenous ghrelin treatment enhances food seeking behaviors as well as drug seeking behaviors. In contrast, mice and rats with mutations to the ghrelin receptor
(Potenza, 2013; Potenza et al., 2013; Wook Koo et al., 2016). Within this system, cells in the mid brain ventral tegmental area (VTA) synthesize and release dopamine into the nucleus accumbens (NAc) and other forebrain and limbic regions, play a significant role in the production of cravings (Anselme & Robinson, 2016; Blum et al., 2015). For instance, this system is stimulated in anticipation to cues that predict availability to reinforcing stimuli, or in response to stressors, and can therefore elicit cravings. Not surprisingly, some suggest that the activity of this system reflects the “wanting” or craving of a particular reinforcer, be it food, sex, drugs of abuse, or gambling (Berridge & Robinson, 2016). The activity of dopamine cells in the VTA and the release of dopamine from these cells into the NAc is modulated by changes in nutritional status. For instance, chronic food restriction enhances, whereas chronic exposure to a high fat diet decreases dopaminergic tone (Cabeza de Vaca & Carr, 1998; Carr, 1996; Carr, Tsimberg, Berman, & Yamamoto, 2003). It is therefore not surprising that most animal models of learning and motivation include food restriction as a means of shaping the behavior of laboratory animals. Furthermore, animal studies probing questions related to addiction show that food restriction enhances the locomotor effects of stimulants and promotes relapse in 116
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other slot machine you might have played, you will have the opportunity to win money. I will start you off with $15. Since this is a penny machine, each credit is worth 1 cent, and you will have 1500 credits to begin with. In the game you will be playing, I will ask you to bet the maximum allowed on the slot machine on each and every spin. Is that understood? Great! this means each and every spin you will be betting 75 credits. This also means you will be betting on all 15 lines and 5 credits per line each spin. This might be a bit confusing for you if you have never played a multi-line slot machine before, don’t worry; there will be a practice session where I will run through it together before you start playing for money. Importantly, the odds of winning are the same as in any casino such as the ones found in our local casinos. Thus, you have the chance to win or lose money. Any amount of money you have left at the end of this session is yours to keep. So, if you end up with 1000 credits, you will take home $10.00. If you end up with 1900 credits, you will take home $19.00. In just a moment, I’m going to take you into the casino room where I have three slot machines. So as to familiarize yourself with these slot machines, I will ask you to do some practice spins to ensure you understand how payoff lines work (it can be complicated). Before I do that, do you have any questions?” Participants were then provided with a brief tutorial on how the slot machine worked, and the experimenter ensured that participants understood the game mechanics. After the instructional, participants were allowed to play on any of the available slot machines, and encouraged to gamble for as long as they liked. Importantly, the outcomes of the slot machine spins were pre-determined, such that all participants could gamble for 25 spins, at which point they were interrupted by the experimenter and asked to complete the subjective craving measures. A third blood sample was also collected at this point. Participants were subsequently informed that they could continue gambling for as long as they liked. Following the methodology of (Cote, Caron, Aubert, Desrochers, & Ladouceur, 2003) and unbeknownst to participants, all subsequent spins were losses. Once participants stopped playing, they were escorted to a second room with desks and asked to fill the cravings questionnaires once again. Next to the questionnaires, the subjects had access to a bowl containing a predetermined number of chocolate snacks (Smarties®) and were told that they could eat as many as they wished while filling the questionnaire. The experimenter left the room and returned 10 min later. At this point, a final blood sample was collected, and participants were then verbally debriefed (they were also provided a written version of the debriefing). As deception was involved in the study, following debriefing, participants were asked to sign a form permitting the use of data for research and teaching purposes. Thereafter, all received $20, a $10 gift card to a local coffee and doughnut shop, and partial credit towards an introductory psychology course for their time (see Fig. 1).
gene (GHSR KO mice and/or rats) show attenuated food and drug seeking behaviors and consumption (Abizaid et al., 2006; Abizaid, 2009; Perello & Dickson, 2015). Recent preclinical evidence shows that ghrelin not only enhances behaviors associated with motivation to obtain food, but also behaviors associated with increased impulsivity as measured by the delay discounting task, a task that measures impulsivity in terms of increased responding for less but more immediate rewards (Anderberg et al., 2016). Furthermore, fasting ghrelin concentrations are associated with increased reward sensitivity and higher scores of impulsivity in human participants (Ralevski et al., 2018). In all, and given that ghrelin is associated with increased impulsivity, these data support the notion that ghrelin not only enhances reward seeking behaviors, but may also enhance gambling behaviors through the stimulation of brain reward systems. One way to demonstrate if this is the case is to determine if plasma ghrelin concentrations are associated with increased motivation to gamble and increased gambling behaviors. Additional support would be provided if ghrelin concentrations were positively associated with the duration of gambling episodes and/or if ghrelin concentrations predict continued betting in the face of repeated loss. These ideas were tested in the current experiment. 1. General methods 1.1. Participants All procedures were approved by Carleton University’s Human Research Ethics Committee. One hundred and one (Females = 37) participants were recruited from a catalogue of gamblers (n = 874) that indicated willingness to participate in gambling-related research and control non- gambling subjects. Using the Problem Gambling Severity Index (PGSI), 12 subjects were categorized as non-problem gamblers (Females = 8), 36 were categorized as low problem gamblers (Females = 14), 35 subjects were categorized as moderate problem gamblers (Females = 10), and 8 of these subjects were scored as pathological gamblers (Females = 2). Participants ranged in age from 17 to 68 years old (M = 20.96, SD = 7.35). 1.2. Procedure All procedures are depicted in Fig. 1. Prior to arriving at the laboratory, participants were provided with explicit instructions regarding their eating schedule for that day. Specifically, half of participants were asked to refrain from eating breakfast before they came into the lab (n = 55; 19 females), while the other half were asked to eat breakfast before coming into the lab (n = 46; 18 females). The experiment was scheduled to start at the time when participants reported eating breakfast. Participants received a Carleton Gambling Lab $15 “gaming” voucher prior to the experiment. This voucher was then ‘cashed’ for credits on the slot machine once they were allowed to play in the slot machines. Upon arriving at the laboratory, participants were provided with an informed consent form, and the experimenter explained to the participant that the purpose of the study was to investigate gambling behavior using slot machines. At this point, a blood sample was collected from each participant. Participants were then asked to complete the craving questionnaires. Once the questionnaires were completed (after ∼15 min), participants were randomly assigned to a cue-exposure (n = 47; 21 females) or control (n = 54; 16 females) conditions. Those in the cue-exposure condition were directed into a casino room (See Fig. 1a), to acclimatize for 2 min to the casino environment. Those in the control condition acclimatized to the laboratory room for 2 min (See Fig. 1b). At this point, a second blood sample was collected. All participants were then directed to the gambling environment to play slots after being provided with the following instructions: “Today you will be playing a multi-line slot machine. Just like any
1.3. Blood ghrelin measurements To collect blood samples, the experimenter produced a small puncture on the side of the index finger of each subject using a springloaded, single-use lancet. Around 200 μl of blood drawn from the puncture using capillary tubes were collected in Sarstedt Microvette® CB 300 K2E tubes coated with EDTA and containing 0.2 μl of HCl 1 N, and a protease inhibitor (PHMB, 10 nM; Cayman Chemicals) to prevent acyl ghrelin degradation. After collection, tubes were placed on ice until centrifugation. At the end of a session, tubes were centrifuged for 5 min at 2000 × g. Centrifuged samples were stored at −80 °C until they were processed for acyl ghrelin content. Acyl ghrelin was analyzed using active human ghrelin ELISA immunodetection kits (Cat # EZRGRA-90 K; Millipore). Samples were assayed in duplicate, and the average intra-assay variability was less than 15%. The lower limit of detectability for active ghrelin in this assay was 7.8 pg/ml. The assay was completed according to the specifications of the manufacturer. Of 117
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ηp2 = 0.448 (see Fig. 2F) than participants that were not fasted compared to non-hungry participants. In contrast, fasted individuals did not differ in any of the sub scales (Anticipation, desire or relief) associated with subjective cravings to gamble scores compared to non-fasted individuals at the onset of the study, suggesting that the fasting protocol we used was not sufficient to increase the baseline motivation to gamble (data not shown; p > 0.05).
the samples collected, we did not analyze samples whose readouts were beyond the lower or higher detection limits of the kit. The total number of subjects with ghrelin samples that were used for analyses was an n = 90. 1.4. Subjective hunger Hunger was assessed the State Food-Craving Questionnaire (SFCQ; Cepeda-Benito, Gleaves, Williams, & Erath, 2000). Analyses included all items in the questionnaire including subscales measuring craving as a physiological state, intense desire to eat, anticipation of relief from negative thoughts, obsessive preoccupation with food, anticipation of positive reinforcement, and self reported hunger. Responses were anchored at 1 (strongly disagree) and 6 (strongly agree). Higher scores on the subscales reflect increased craving for food.
2.2. Gambling cues specifically increased ghrelin concentrations regardless of feeding condition Given that the overnight fast was able to increase subjective food craving scores, we examined the effects of the fast on plasma acyl ghrelin concentrations, and if acyl ghrelin concentrations would also be influenced by cues predicting imminent opportunity to gamble. To examine this, we first conducted a mixed factorial ANOVA with cue (control vs. casino) and feeding manipulation (control vs fasted) as the between groups variables, and ghrelin (samples 1, 2, 3 and 4) as the within groups variable. Results from this analysis showed a significant cue x ghrelin interaction effect (F(3,258) = 2.929, p = 0.034, ηp2 = 0.033), where casino cues significantly increased acyl ghrelin concentrations. Simple effect analyses showed that the effect of the casino cues was significant at the final sampling point where subjects in the fasted/cued group had significantly higher acyl-ghrelin levels compared to non-fasted/cued group (p < .0005) and the fed/non-cued control groups (p < 0.05). Fed /cued subject showed an increase in ghrelin concentrations but these were not significantly different from those seen in fed/non cued subjects by the last sampling episode (p < 0.05). In contrast, neither fasting nor the cues were effective in increasing subjective measures of gambling cravings, including measures of anticipation, desire, or relief (p < 0.05), suggesting that the fasting protocol nor the cues we used affected the subjective measures of motivation to gamble in a detectable manner in this study.
1.5. Subjective cravings to gamble Craving to gamble was assessed using the gambling-related craving scale (GACS: Young & Wohl, 2009). Participants were asked to complete a series of 9 items, indicating how much they agreed with questions assessing different aspects of the craving experience. Responses were given using a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). The GACS is comprised of three subscales. The first, the anticipation subscale, consists of 3 items (α = .74) that assess craving for the anticipation of positive affect from gambling (e.g., “Gambling would be fun right now”). The desire subscale contains 3 items (α = .85) that assess craving for the immediate desire to gamble (e.g., “I need to gamble now”). Finally, the relief subscale contains 3 items (α = .80) and measures craving for relief from negative affect from gambling (e.g., “If I were gambling now I could think more clearly”). 1.6. Gambling persistence (spins) Gambling persistence was operationally defined as the number of slot spins played by participants after continuous loss (Cote et al., 2003).
2.3. Plasma acyl ghrelin concentrations predict gambling persistance Following the collection of the third blood sample, participants were allowed to gamble and were tested for gambling persistence in the face of loss. A 2 × 2 between groups ANOVA found no significant differences between the different groups in the number of spins subjects were willing to perform in the face of loss (non-significant interaction effect, F(3,90) = 0.216, p > 0.05; see Fig. 4A). Regression analyses, however, showed that plasma acyl ghrelin concentrations 20 min after the gambling cues were presented (ghrelin concentration in the third sample) were a positive predictor of spins in the face of continued loss and regardless of the experimental group that the subjects were in (R2 = 0.05, b = 0.01, SE = 0.005, p. < 0.05.). Specifically, gamblers with higher levels of circulating acyl ghrelin in their blood gambled more in face of loss (See Fig. 4B). Acyl ghrelin concentrations 2 min after the presentation of gambling cues were presented (ghrelin concentrations from the second sample) were also a positive predictor of gambling persistence but this association did not attain statistical significance (R2 = 0.037, b = 0.015, SE = 0.008, p = 0.068). A 2 × 2 between groups ANOVA was used to analyze group differences in the number of smarties consumed at the end of the study. This analysis showed no significant group differences in the number of smarties consumed (non-significant interaction effect, F(3,90) = 1.21, p > 0.05). In addition, plasma acyl ghrelin concentrations were not significantly associated with the number of smarties consumed at the end of study (p > 0.05)
2. Results 2.1. Fasting increases subjective hunger scores but not subjective cravings to gamble To determine if the feeding manipulation was effective in increasing food motivation, we examined differences in scores in the SFCQ obtained from fasted vs non-fasted participants at the outset of the study. These are depicted in Fig. 2. A one-way ANOVA was conducted on the physiological hunger subscale of the SFCQ. Results revealed that those in the hungry condition had higher scores on hunger for food as a physiological state compared to those in the not-hungry condition, F (1,99) = 88.88, p < 0.001, ηp2 = .47 (see Fig. 2A). A similar ANOVA was conducted on scores from the subscale measuring self-reported desire to eat foods. Results from these analyses revealed that those in the hungry condition reported a more intense desire to eat compared to those participants that were not fasted overnight, F(1,99) = 15.56, p < 0.01, ηp2 = .136 (see Fig. 2B). Analyses on scores from the anticipation subscale of the SFCQ showed that fasted participants had higher food anticipation scores compared to non-fasted participants, F (1,99) = 32.61, p =0.05, ηp2 = .25 (see Fig. 2C). Fasted participants also showed significantly higher scores on preoccupation of lack of control over eating than non-fasted participants, F(1,99) = 10.62, p < 0.01, ηp2 = .097 (see Fig. 2D). Finally, one way ANOVAs revealed that fasted participants reported significant higher scores for positive reinforcement anticipation, F(1,99) = 10.43, p < 0.01, ηp2 = 0.95 (Fig. 2E) and higher self-reported hunger, F(1,99) = 79.65, p < 0.001,
3. Discussion In this study we investigated the potential association between selfreported hunger, craving to gamble, and circulating acyl-ghrelin plasma 118
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Fig. 2. Fasting increases subjective food craving measures. The overnight fasting manipulation was effective in significantly increasing scores in all of the food craving measures investigated including cravings as a physiological state (Fig. 2A), intense desire to eat (Fig. 2B), anticipation of relief from negative thoughts (Fig. 2C), obsessive preoccupation with food (Fig. 2D), anticipation of positive reinforcement (Fig. 2E), and self-reported hunger (Fig. 2F). *= p < 0.05.
schedules where time of the day becomes a cue predicting food (I. D. Blum et al., 2009; LeSauter, Hoque, Weintraub, Pfaff, & Silver, 2009). This has also been reported in preclinical models of drug self-administration where cues predicting cocaine availability correlate with an increase in plasma ghrelin concentrations (Tessari et al., 2007). Furthermore, mice lacking ghrelin receptors or treated with ghrelin receptor antagonists show deficits in cue induced feeding even in the absence or food restriction (St-Onge et al., 2016; Walker, Ibia, & Zigman, 2012). Together these data support the idea that ghrelin concentrations increase in response to cues that predict the opportunity to engage in reinforcing behavior including gambling. Importantly, plasma acyl ghrelin concentrations at the end of the study were highest in those participants that were fasted overnight. Ghrelin is a metabolic hormone associated with increased appetite, and concentrations of this hormone are elevated following caloric restriction (Toshinai et al., 2001). In the current study, however, our fasting manipulation was not sufficient to increase baseline plasma acylghrelin concentrations significantly. It seems, however, that this manipulation enhanced the effect of the gambling cued exposure and
concentrations with gambling behavior in humans. There were three major findings associated with this study. The first is that, regardless of feeding status, cues associated with gambling increased ghrelin concentrations. Importantly, by the end of the study, those subjects that were fasted prior to the study, and then were presented a cue, had the highest ghrelin concentrations. The second major finding was that acyl ghrelin concentrations prior to gambling were the best predictor of gambling persistence in the face of loss. Finally, acyl ghrelin concentrations prior to gambling were a better predictor than previously used subjective gambling craving measures. Perhaps the most significant finding in this study is that the presentation of cues that predict the resulted in a sharp increase in ghrelin secretion in our participants. Moreover, the effects of cues on ghrelin concentrations were more pronounced and longer lasting in participants that had been fasted overnight in spite of the fasting protocol not being effective in increasing baseline ghrelin levels. Similar increases in ghrelin concentrations have been reported in studies where human participants are shown palatable food images (Schussler et al., 2012), and in studies where humans and animals are placed under feeding
Fig. 3. Gambling cues were effective in increasing ghrelin concentrations especially in participants that fasted overnight. Fig. 3A shows that overall, ghrelin levels increased throughout the experimental session. As seen in Fig. 3B, the fasting protocol was not sufficiently strong to increase baseline ghrelin concentrations (acyl ghrelin concentrations at the onset of the study, p. > 0.05). *= p < 0.05. By the end of the study, however, it was clear that those subjects that had been fasted and that were presented gambling cues, had the highest plasma concentrations of acyl ghrelin (p. < 0.05; Fig. 3C). 119
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Fig. 4. Ghrelin concentrations 20 min after the gambling cue were the best predictors of gambling persistence. Fig. 4A shows that there were no significant differences in gambling persistence between experimental groups (p. > 0.05). Ghrelin concentrations after the gambling cues were the best predictor of gambling persistence regardless of experimental groups. Thus, the higher the ghrelin concentrations, the more likely subjects gambled in the face of continued loss (p. < 0.05).
predictors of persistent gambling in the face of continued loss in this experiment. While this was unexpected, it is likely that subjective gambling craving measures are more sensitive when used with pathological gamblers, a subgroup of individuals that were poorly represented in our sample. Alternatively, it is possible that the blood collection somewhat affected the way in which the participants responded to the questionnaires, somewhat inhibiting their self-reports of cravings, but not their actual behavioral responses. Nevertheless, and regardless of these potential discrepancies, ghrelin concentrations may actually be better predictors of gambling persistence and of potential for pathological gambling. Future studies should be conducted using pathological gamblers to determine if this is the case. Overall, our study represents the first attempt to examine the association between acyl ghrelin concentrations on gambling behavior under laboratory conditions that closely mimic a casino environment. Moreover, our data also supports previous pre-clinical data using the differential reinforcement of low rate task (DRL), a task where animals are only reinforced when the ratio between rewarded response and total responses is used to measure impulsive behaviors. Animals are considered more impulsive when they produce responses in spite of these not being reinforced, and therefore decreasing this ratio. In this study, rats infused with ghrelin into the ventricles or into the VTA had a lower DRL ratio, suggesting that these rats, like our subjects, were more likely to produce behavioral responses in spite of not being awarded a reinforcer (Anderberg et al., 2016). Similarly, our data is in line with recent study showing that fasting ghrelin concentrations in human experiment participants are associated not only with increased reward
ultimately resulted in average ghrelin concentrations that were about 25% higher than those seen in subjects in the other groups. Thus, while the fasting manipulation may not have worked as expected, it did seem to sensitize the ghrelin response to the gambling cue. This potentially could be mediated by increasing sympathetic tone that could increase interoceptive awareness of the gambling cues while also directly increasing ghrelin secretion (Herbert et al., 2012; Zhao et al., 2010) Given that the gambling cues increased plasma acyl ghrelin concentrations especially in fasted individuals, we expected that these individuals would also gamble the most in spite of persistent loss. Our results failed to support this. Nevertheless, and regardless of the experimental group, acyl ghrelin concentrations just prior to the gambling persistence test were the best predictor of continued gambling in the face of loss. This somewhat paradoxical effect might be related to the timing of the gambling persistence task in relation to the increases in ghrelin secretion following the gambling cue. As seen in Fig. 2, ghrelin concentrations peaked at 20 min after the presentation of the cue and remained higher in subjects that had been asked to fast overnight until the end of the study. Gambling behavior, however, was assessed in between these two time points. It is therefore likely that gambling behaviors in cued fasted subjects would have been higher than cued nonfasted participants if the testing had been conducted later in the experiment when the levels of ghrelin between these subjects were significantly different. Interestingly, while subjective measures of gambling cravings have been successfully validated as a reliable tool to predict gambling behavior (Wohl, Young, & Hart, 2007), ghrelin concentrations were better 120
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dopaminergic system, to be considered as potential targets for the treatment of behavioral addictions including gambling.
sensitivity, but also with increased scores in impulsivity measures (Ralevski et al., 2018). These results are also in line with data from studies linking novelty seeking and polymorphisms of the ghrelin receptor (Hansson et al., 2012). Interestingly, reward sensitivity, impulsivity and novelty seeking are traits highly associated with pathological gambling (Black et al., 2015; Goudriaan, Oosterlaan, de Beurs, & Van den Brink, 2004; Sztainert, Wohl, McManus, & Stead, 2014; Verdejo-Garcia, Lawrence, & Clark, 2008). There are, however, several limitations to this study that need to be acknowledged. For instance, and as mentioned above, our fasting protocol was not sufficient to increase ghrelin concentrations at the onset of the study. One could explain this as potential lack of compliance by some of the subjects, or that an overnight fast is not sufficient to increase ghrelin concentrations in human subjects. Nevertheless, fasted participants did show ghrelin concentrations that increased following the cue and that, in contrast to non-fasted participants, remained elevated until the end of the study. Perhaps the fasting protocol was not sufficient to increase basal ghrelin concentrations but sensitized ghrelin secretion in response to the gambling cues. Another limitation to our study was that we did not examine sex differences in our measures. The number of participants in this study, especially female participants, was not sufficient to allow for sex to be included as a variable. We do acknowledge this as a limitation, especially considering data clearly showing that gambling behavior is different in females vs males (Nower & Blaszczynski, 2006; van den Bos et al., 2013), and that, at least in preclinical studies, there are sex differences in the behavioral effects of ghrelin(Bagheri et al., 2015; Soriano-Guillen et al., 2016; Yamada et al., 2015). This is a topic currently being examined in our laboratory. Similarly, the number of subjects that could be considered problem gamblers was not sufficient to determine if this group would be a strong predictor of gambling persistence and of ghrelin secretion in response to cues, a limitation that is currently being considered for future studies. In addition to gambling, the secretion of ghrelin has been linked to increased motivation to obtain palatable foods, sex, alcohol, nicotine and other drugs of abuse in part through the stimulation of dopamine cells in the VTA (Abizaid, 2009; Perello & Dickson, 2015; Zallar, Farokhnia, Tunstall, Vendruscolo, & Leggio, 2017). Within the VTA, ghrelin stimulates dopamine cell activity, and the release of dopamine into a number of forebrain regions to facilitate reward seeking, contextual reward memories, and reinforcement (Chuang et al., 2011; Dickson et al., 2010; Hyland et al., 2018; Jerlhag et al., 2007; Kanoski, Fortin, Ricks, & Grill, 2013; King et al., 2011; Skibicka, Hansson, Alvarez-Crespo, Friberg, & Dickson, 2011; St-Onge et al., 2016; Wellman et al., 2012). Indeed, ghrelin intravenous injections to human participants enhanced the activity of brain centers associated with positive valence including the VTA and NAc, in response to images depicting palatable foods (Malik, McGlone, Bedrossian, & Dagher, 2008). Nevertheless, similar imaging studies where ghrelin is injected to gambling participants and using images associated with gambling have yet to be conducted. The present findings are compelling on a few fronts. First, they point to ghrelin as a potential target for a pharmacological treatment that reduces cravings produced by gambling associated cues in the same way that ghrelin and its receptor are currently targets to curb alcohol cravings (Leggio et al., 2014). For instance, ghrelin receptor antagonists may represent a means of reducing cravings in response to gambling cues in pathological gambling individuals. Findings also suggest that low cost preventive manipulations could be used to curb gambling and facilitate responsible gambling—manipulations like providing free or low cost food at a gambling venues to minimize the possibility that players are gambling on an empty stomach. More importantly, these data open the door to alternatives where metabolic signals like ghrelin and others like leptin and glucagon-like peptide 1 (GLP-1) (Hernandez et al., 2018; Kanoski, Hayes, & Skibicka, 2016; Schmidt et al., 2016; Shirazi, Dickson, & Skibicka, 2013), that also target the mesolimbic
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Hungry to gamble? Ghrelin as a predictor of persistent gambling in the face of loss Travis Sztainerta, Rebecca Hayb, Michael J.A. Wohla, Alfonso Abizaidb, a b
T
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Carleton University Department of Psychology, Canada Carleton University Department of Neuroscience, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Ghrelin Feeding Cravings Gambling Addiction Reward Behavior
Ghrelin, a peptide hormone associated with appetite, is also linked to increased reward seeking behaviors, including food, sex, and drug seeking behaviors through the stimulation of the mesolimbic dopaminergic system. Moreover, plasma ghrelin concentrations are increased by cues that predict rewards, suggesting that cues could facilitate cravings and ultimately relapse. In this project we examined the effects of an overnight fast, a manipulation known to increase ghrelin concentrations, on gambling behaviors. We also examined if cues associated with gambling would also increase ghrelin and, if so, we examined if these increases were associated with gambling behavior. One hundred and one (37 females) participants were asked to fast overnight or after breakfast and then asked to complete food and gambling craving questionnaires. Participants were then presented with gambling cues (a casino like environment in the lab) or a control cue (a cubicle with a computer). After the cue, subjects filled gambling craving questionnaires, and were allowed to gamble. Following 25 practice spins, the slot machines were fixed so that all subsequent spins were losses, and the number of spins in spite of losses were quantified. Blood samples were collected throughout the experiment. Results showed that the gambling cues significantly increased ghrelin concentrations particularly in fasted individuals, and that ghrelin concentrations 20 min after the cue were the best predictor for gambling persistence in the face of continued loss (p < 0.05). Our results suggest that cues that predict the opportunity to gamble have an acute effect on ghrelin concentrations that is facilitated by fasting, and that ghrelin concentrations are a significant predictor of gambling persistence.
Gambling is a legal and increasingly socially acceptable activity in most parts of the world (see (Cosgrave & Klassen, 2001). However, a subset of players (1–2% of the population) develop a gambling disorder, which is associated with an array of social, legal and psychological problems (Nautiyal, Okuda, Hen, & Blanco, 2017; Potenza et al., 2013; Potenza, 2014). This is because disordered gamblers spend an excessive amount of money gambling, even in the face of continued loss (LaPlante, Nelson, LaBrie, & Shaffer, 2011; Young, Wohl, Matheson, Baumann, & Anisman, 2008). In general, it is thought that pathways to disordered gambling include the positive valance attributed to successful gambles (i.e., reinforcement) and the engrossing nature of gambling games that helps relieve negative affective (or valance) states (Blaszczynski & Nower, 2002; Young & Wohl, 2009). As a result, despite the negative consequences of continued gambling, many gamblers experience an overwhelming, often irresistible, craving to gamble (Sharpe, 2002). Recent interest in gambling-related cravings has yielded the
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development of several single-item as well as multi-item questionnaires specifically designed to assess the subjective experience of craving gamble. For example, the Gambling Craving Scale (Young & Wohl, 2009) is a valid psychometric tool to assess negative and positive valance dimensions associated with cravings and also associated with the tendency of disordered gamblers to continue gambling despite continuous losses. Although there are several reliable psychometric measures like the GACS that can be used to detect and predict pathological gambling, the relationship between craving, and biological markers or substrates underlying gambling cravings have not been clearly established. The present experiment addressed this gap by examining whether craving to gamble is associated with biological markers associated with risk taking to predict excessive gambling. There is extensive literature in preclinical studies that link cravings in direct association with activity of the mesolimbic dopaminergic system, a neural network that is critical for reward seeking behaviors (positive valence) and that is also active in response to stressors
Corresponding author. E-mail address: [email protected] (A. Abizaid).
https://doi.org/10.1016/j.biopsycho.2018.10.011 Received 23 March 2018; Received in revised form 18 October 2018; Accepted 18 October 2018 Available online 28 October 2018 0301-0511/ © 2018 Elsevier B.V. All rights reserved.
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Fig. 1. Experimental design and casino gambling cues used as an independent variable. Fig. 1A depicts the experimental design used in the current study, where subjects were asked to participate in the experiment soon after they consumed breakfast or following an overnight fast (independent variable 1). After a series or questionnaires and blood samples, subjects were presented with either a gambling cue (the casino environment) or no gambling cues (a desk with a computer; independent variable 2, Fig. 1B). A blood sample was collected 20 min following the presentation of the cue and participants were tested for gambling persistence.
heroin and cocaine self-administration studies (Cabeza de Vaca & Carr, 1998; D’Cunha, Sedki, Macri, Casola, & Shalev, 2013). In correlation with this, food restriction also causes an increase in the secretion of the hormone ghrelin, a signal linked to metabolic status and reward seeking behaviors (Abizaid, 2009; Edwards & Abizaid, 2016). Receptors for ghrelin are detected in several hypothalamic and extra hypothalamic regions important for feeding and for reward seeking behaviors including the VTA (Guan et al., 1997; Mani et al., 2014; Zigman, Jones, Lee, Saper, & Elmquist, 2006). Ghrelin acts on these regions to promote reward seeking behaviors (King, Isaacs, O’Farrell, & Abizaid, 2011; Wellman, Davis, & Nation, 2005, 2011; Wellman et al., 2012; Wellman, Clifford, & Rodriguez, 2013), whereas ghrelin receptor antagonists or mutations to the ghrelin receptor lead to reduced reward seeking behaviors(Chuang et al., 2011; Jerlhag & Engel, 2011; Jerlhag, Egecioglu, Dickson, & Engel, 2010; Jerlhag, Landgren, Egecioglu, Dickson, & Engel, 2011; Perello & Zigman, 2012; Salome et al., 2009; Skibicka, Hansson, Egecioglu, & Dickson, 2012; St-Onge, Watts, & Abizaid, 2016; Suchankova, Steensland, Fredriksson, Engel, & Jerlhag, 2013; Verhagen et al., 2011). Thus, just like food restriction, exogenous ghrelin treatment enhances food seeking behaviors as well as drug seeking behaviors. In contrast, mice and rats with mutations to the ghrelin receptor
(Potenza, 2013; Potenza et al., 2013; Wook Koo et al., 2016). Within this system, cells in the mid brain ventral tegmental area (VTA) synthesize and release dopamine into the nucleus accumbens (NAc) and other forebrain and limbic regions, play a significant role in the production of cravings (Anselme & Robinson, 2016; Blum et al., 2015). For instance, this system is stimulated in anticipation to cues that predict availability to reinforcing stimuli, or in response to stressors, and can therefore elicit cravings. Not surprisingly, some suggest that the activity of this system reflects the “wanting” or craving of a particular reinforcer, be it food, sex, drugs of abuse, or gambling (Berridge & Robinson, 2016). The activity of dopamine cells in the VTA and the release of dopamine from these cells into the NAc is modulated by changes in nutritional status. For instance, chronic food restriction enhances, whereas chronic exposure to a high fat diet decreases dopaminergic tone (Cabeza de Vaca & Carr, 1998; Carr, 1996; Carr, Tsimberg, Berman, & Yamamoto, 2003). It is therefore not surprising that most animal models of learning and motivation include food restriction as a means of shaping the behavior of laboratory animals. Furthermore, animal studies probing questions related to addiction show that food restriction enhances the locomotor effects of stimulants and promotes relapse in 116
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other slot machine you might have played, you will have the opportunity to win money. I will start you off with $15. Since this is a penny machine, each credit is worth 1 cent, and you will have 1500 credits to begin with. In the game you will be playing, I will ask you to bet the maximum allowed on the slot machine on each and every spin. Is that understood? Great! this means each and every spin you will be betting 75 credits. This also means you will be betting on all 15 lines and 5 credits per line each spin. This might be a bit confusing for you if you have never played a multi-line slot machine before, don’t worry; there will be a practice session where I will run through it together before you start playing for money. Importantly, the odds of winning are the same as in any casino such as the ones found in our local casinos. Thus, you have the chance to win or lose money. Any amount of money you have left at the end of this session is yours to keep. So, if you end up with 1000 credits, you will take home $10.00. If you end up with 1900 credits, you will take home $19.00. In just a moment, I’m going to take you into the casino room where I have three slot machines. So as to familiarize yourself with these slot machines, I will ask you to do some practice spins to ensure you understand how payoff lines work (it can be complicated). Before I do that, do you have any questions?” Participants were then provided with a brief tutorial on how the slot machine worked, and the experimenter ensured that participants understood the game mechanics. After the instructional, participants were allowed to play on any of the available slot machines, and encouraged to gamble for as long as they liked. Importantly, the outcomes of the slot machine spins were pre-determined, such that all participants could gamble for 25 spins, at which point they were interrupted by the experimenter and asked to complete the subjective craving measures. A third blood sample was also collected at this point. Participants were subsequently informed that they could continue gambling for as long as they liked. Following the methodology of (Cote, Caron, Aubert, Desrochers, & Ladouceur, 2003) and unbeknownst to participants, all subsequent spins were losses. Once participants stopped playing, they were escorted to a second room with desks and asked to fill the cravings questionnaires once again. Next to the questionnaires, the subjects had access to a bowl containing a predetermined number of chocolate snacks (Smarties®) and were told that they could eat as many as they wished while filling the questionnaire. The experimenter left the room and returned 10 min later. At this point, a final blood sample was collected, and participants were then verbally debriefed (they were also provided a written version of the debriefing). As deception was involved in the study, following debriefing, participants were asked to sign a form permitting the use of data for research and teaching purposes. Thereafter, all received $20, a $10 gift card to a local coffee and doughnut shop, and partial credit towards an introductory psychology course for their time (see Fig. 1).
gene (GHSR KO mice and/or rats) show attenuated food and drug seeking behaviors and consumption (Abizaid et al., 2006; Abizaid, 2009; Perello & Dickson, 2015). Recent preclinical evidence shows that ghrelin not only enhances behaviors associated with motivation to obtain food, but also behaviors associated with increased impulsivity as measured by the delay discounting task, a task that measures impulsivity in terms of increased responding for less but more immediate rewards (Anderberg et al., 2016). Furthermore, fasting ghrelin concentrations are associated with increased reward sensitivity and higher scores of impulsivity in human participants (Ralevski et al., 2018). In all, and given that ghrelin is associated with increased impulsivity, these data support the notion that ghrelin not only enhances reward seeking behaviors, but may also enhance gambling behaviors through the stimulation of brain reward systems. One way to demonstrate if this is the case is to determine if plasma ghrelin concentrations are associated with increased motivation to gamble and increased gambling behaviors. Additional support would be provided if ghrelin concentrations were positively associated with the duration of gambling episodes and/or if ghrelin concentrations predict continued betting in the face of repeated loss. These ideas were tested in the current experiment. 1. General methods 1.1. Participants All procedures were approved by Carleton University’s Human Research Ethics Committee. One hundred and one (Females = 37) participants were recruited from a catalogue of gamblers (n = 874) that indicated willingness to participate in gambling-related research and control non- gambling subjects. Using the Problem Gambling Severity Index (PGSI), 12 subjects were categorized as non-problem gamblers (Females = 8), 36 were categorized as low problem gamblers (Females = 14), 35 subjects were categorized as moderate problem gamblers (Females = 10), and 8 of these subjects were scored as pathological gamblers (Females = 2). Participants ranged in age from 17 to 68 years old (M = 20.96, SD = 7.35). 1.2. Procedure All procedures are depicted in Fig. 1. Prior to arriving at the laboratory, participants were provided with explicit instructions regarding their eating schedule for that day. Specifically, half of participants were asked to refrain from eating breakfast before they came into the lab (n = 55; 19 females), while the other half were asked to eat breakfast before coming into the lab (n = 46; 18 females). The experiment was scheduled to start at the time when participants reported eating breakfast. Participants received a Carleton Gambling Lab $15 “gaming” voucher prior to the experiment. This voucher was then ‘cashed’ for credits on the slot machine once they were allowed to play in the slot machines. Upon arriving at the laboratory, participants were provided with an informed consent form, and the experimenter explained to the participant that the purpose of the study was to investigate gambling behavior using slot machines. At this point, a blood sample was collected from each participant. Participants were then asked to complete the craving questionnaires. Once the questionnaires were completed (after ∼15 min), participants were randomly assigned to a cue-exposure (n = 47; 21 females) or control (n = 54; 16 females) conditions. Those in the cue-exposure condition were directed into a casino room (See Fig. 1a), to acclimatize for 2 min to the casino environment. Those in the control condition acclimatized to the laboratory room for 2 min (See Fig. 1b). At this point, a second blood sample was collected. All participants were then directed to the gambling environment to play slots after being provided with the following instructions: “Today you will be playing a multi-line slot machine. Just like any
1.3. Blood ghrelin measurements To collect blood samples, the experimenter produced a small puncture on the side of the index finger of each subject using a springloaded, single-use lancet. Around 200 μl of blood drawn from the puncture using capillary tubes were collected in Sarstedt Microvette® CB 300 K2E tubes coated with EDTA and containing 0.2 μl of HCl 1 N, and a protease inhibitor (PHMB, 10 nM; Cayman Chemicals) to prevent acyl ghrelin degradation. After collection, tubes were placed on ice until centrifugation. At the end of a session, tubes were centrifuged for 5 min at 2000 × g. Centrifuged samples were stored at −80 °C until they were processed for acyl ghrelin content. Acyl ghrelin was analyzed using active human ghrelin ELISA immunodetection kits (Cat # EZRGRA-90 K; Millipore). Samples were assayed in duplicate, and the average intra-assay variability was less than 15%. The lower limit of detectability for active ghrelin in this assay was 7.8 pg/ml. The assay was completed according to the specifications of the manufacturer. Of 117
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ηp2 = 0.448 (see Fig. 2F) than participants that were not fasted compared to non-hungry participants. In contrast, fasted individuals did not differ in any of the sub scales (Anticipation, desire or relief) associated with subjective cravings to gamble scores compared to non-fasted individuals at the onset of the study, suggesting that the fasting protocol we used was not sufficient to increase the baseline motivation to gamble (data not shown; p > 0.05).
the samples collected, we did not analyze samples whose readouts were beyond the lower or higher detection limits of the kit. The total number of subjects with ghrelin samples that were used for analyses was an n = 90. 1.4. Subjective hunger Hunger was assessed the State Food-Craving Questionnaire (SFCQ; Cepeda-Benito, Gleaves, Williams, & Erath, 2000). Analyses included all items in the questionnaire including subscales measuring craving as a physiological state, intense desire to eat, anticipation of relief from negative thoughts, obsessive preoccupation with food, anticipation of positive reinforcement, and self reported hunger. Responses were anchored at 1 (strongly disagree) and 6 (strongly agree). Higher scores on the subscales reflect increased craving for food.
2.2. Gambling cues specifically increased ghrelin concentrations regardless of feeding condition Given that the overnight fast was able to increase subjective food craving scores, we examined the effects of the fast on plasma acyl ghrelin concentrations, and if acyl ghrelin concentrations would also be influenced by cues predicting imminent opportunity to gamble. To examine this, we first conducted a mixed factorial ANOVA with cue (control vs. casino) and feeding manipulation (control vs fasted) as the between groups variables, and ghrelin (samples 1, 2, 3 and 4) as the within groups variable. Results from this analysis showed a significant cue x ghrelin interaction effect (F(3,258) = 2.929, p = 0.034, ηp2 = 0.033), where casino cues significantly increased acyl ghrelin concentrations. Simple effect analyses showed that the effect of the casino cues was significant at the final sampling point where subjects in the fasted/cued group had significantly higher acyl-ghrelin levels compared to non-fasted/cued group (p < .0005) and the fed/non-cued control groups (p < 0.05). Fed /cued subject showed an increase in ghrelin concentrations but these were not significantly different from those seen in fed/non cued subjects by the last sampling episode (p < 0.05). In contrast, neither fasting nor the cues were effective in increasing subjective measures of gambling cravings, including measures of anticipation, desire, or relief (p < 0.05), suggesting that the fasting protocol nor the cues we used affected the subjective measures of motivation to gamble in a detectable manner in this study.
1.5. Subjective cravings to gamble Craving to gamble was assessed using the gambling-related craving scale (GACS: Young & Wohl, 2009). Participants were asked to complete a series of 9 items, indicating how much they agreed with questions assessing different aspects of the craving experience. Responses were given using a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). The GACS is comprised of three subscales. The first, the anticipation subscale, consists of 3 items (α = .74) that assess craving for the anticipation of positive affect from gambling (e.g., “Gambling would be fun right now”). The desire subscale contains 3 items (α = .85) that assess craving for the immediate desire to gamble (e.g., “I need to gamble now”). Finally, the relief subscale contains 3 items (α = .80) and measures craving for relief from negative affect from gambling (e.g., “If I were gambling now I could think more clearly”). 1.6. Gambling persistence (spins) Gambling persistence was operationally defined as the number of slot spins played by participants after continuous loss (Cote et al., 2003).
2.3. Plasma acyl ghrelin concentrations predict gambling persistance Following the collection of the third blood sample, participants were allowed to gamble and were tested for gambling persistence in the face of loss. A 2 × 2 between groups ANOVA found no significant differences between the different groups in the number of spins subjects were willing to perform in the face of loss (non-significant interaction effect, F(3,90) = 0.216, p > 0.05; see Fig. 4A). Regression analyses, however, showed that plasma acyl ghrelin concentrations 20 min after the gambling cues were presented (ghrelin concentration in the third sample) were a positive predictor of spins in the face of continued loss and regardless of the experimental group that the subjects were in (R2 = 0.05, b = 0.01, SE = 0.005, p. < 0.05.). Specifically, gamblers with higher levels of circulating acyl ghrelin in their blood gambled more in face of loss (See Fig. 4B). Acyl ghrelin concentrations 2 min after the presentation of gambling cues were presented (ghrelin concentrations from the second sample) were also a positive predictor of gambling persistence but this association did not attain statistical significance (R2 = 0.037, b = 0.015, SE = 0.008, p = 0.068). A 2 × 2 between groups ANOVA was used to analyze group differences in the number of smarties consumed at the end of the study. This analysis showed no significant group differences in the number of smarties consumed (non-significant interaction effect, F(3,90) = 1.21, p > 0.05). In addition, plasma acyl ghrelin concentrations were not significantly associated with the number of smarties consumed at the end of study (p > 0.05)
2. Results 2.1. Fasting increases subjective hunger scores but not subjective cravings to gamble To determine if the feeding manipulation was effective in increasing food motivation, we examined differences in scores in the SFCQ obtained from fasted vs non-fasted participants at the outset of the study. These are depicted in Fig. 2. A one-way ANOVA was conducted on the physiological hunger subscale of the SFCQ. Results revealed that those in the hungry condition had higher scores on hunger for food as a physiological state compared to those in the not-hungry condition, F (1,99) = 88.88, p < 0.001, ηp2 = .47 (see Fig. 2A). A similar ANOVA was conducted on scores from the subscale measuring self-reported desire to eat foods. Results from these analyses revealed that those in the hungry condition reported a more intense desire to eat compared to those participants that were not fasted overnight, F(1,99) = 15.56, p < 0.01, ηp2 = .136 (see Fig. 2B). Analyses on scores from the anticipation subscale of the SFCQ showed that fasted participants had higher food anticipation scores compared to non-fasted participants, F (1,99) = 32.61, p =0.05, ηp2 = .25 (see Fig. 2C). Fasted participants also showed significantly higher scores on preoccupation of lack of control over eating than non-fasted participants, F(1,99) = 10.62, p < 0.01, ηp2 = .097 (see Fig. 2D). Finally, one way ANOVAs revealed that fasted participants reported significant higher scores for positive reinforcement anticipation, F(1,99) = 10.43, p < 0.01, ηp2 = 0.95 (Fig. 2E) and higher self-reported hunger, F(1,99) = 79.65, p < 0.001,
3. Discussion In this study we investigated the potential association between selfreported hunger, craving to gamble, and circulating acyl-ghrelin plasma 118
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Fig. 2. Fasting increases subjective food craving measures. The overnight fasting manipulation was effective in significantly increasing scores in all of the food craving measures investigated including cravings as a physiological state (Fig. 2A), intense desire to eat (Fig. 2B), anticipation of relief from negative thoughts (Fig. 2C), obsessive preoccupation with food (Fig. 2D), anticipation of positive reinforcement (Fig. 2E), and self-reported hunger (Fig. 2F). *= p < 0.05.
schedules where time of the day becomes a cue predicting food (I. D. Blum et al., 2009; LeSauter, Hoque, Weintraub, Pfaff, & Silver, 2009). This has also been reported in preclinical models of drug self-administration where cues predicting cocaine availability correlate with an increase in plasma ghrelin concentrations (Tessari et al., 2007). Furthermore, mice lacking ghrelin receptors or treated with ghrelin receptor antagonists show deficits in cue induced feeding even in the absence or food restriction (St-Onge et al., 2016; Walker, Ibia, & Zigman, 2012). Together these data support the idea that ghrelin concentrations increase in response to cues that predict the opportunity to engage in reinforcing behavior including gambling. Importantly, plasma acyl ghrelin concentrations at the end of the study were highest in those participants that were fasted overnight. Ghrelin is a metabolic hormone associated with increased appetite, and concentrations of this hormone are elevated following caloric restriction (Toshinai et al., 2001). In the current study, however, our fasting manipulation was not sufficient to increase baseline plasma acylghrelin concentrations significantly. It seems, however, that this manipulation enhanced the effect of the gambling cued exposure and
concentrations with gambling behavior in humans. There were three major findings associated with this study. The first is that, regardless of feeding status, cues associated with gambling increased ghrelin concentrations. Importantly, by the end of the study, those subjects that were fasted prior to the study, and then were presented a cue, had the highest ghrelin concentrations. The second major finding was that acyl ghrelin concentrations prior to gambling were the best predictor of gambling persistence in the face of loss. Finally, acyl ghrelin concentrations prior to gambling were a better predictor than previously used subjective gambling craving measures. Perhaps the most significant finding in this study is that the presentation of cues that predict the resulted in a sharp increase in ghrelin secretion in our participants. Moreover, the effects of cues on ghrelin concentrations were more pronounced and longer lasting in participants that had been fasted overnight in spite of the fasting protocol not being effective in increasing baseline ghrelin levels. Similar increases in ghrelin concentrations have been reported in studies where human participants are shown palatable food images (Schussler et al., 2012), and in studies where humans and animals are placed under feeding
Fig. 3. Gambling cues were effective in increasing ghrelin concentrations especially in participants that fasted overnight. Fig. 3A shows that overall, ghrelin levels increased throughout the experimental session. As seen in Fig. 3B, the fasting protocol was not sufficiently strong to increase baseline ghrelin concentrations (acyl ghrelin concentrations at the onset of the study, p. > 0.05). *= p < 0.05. By the end of the study, however, it was clear that those subjects that had been fasted and that were presented gambling cues, had the highest plasma concentrations of acyl ghrelin (p. < 0.05; Fig. 3C). 119
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Fig. 4. Ghrelin concentrations 20 min after the gambling cue were the best predictors of gambling persistence. Fig. 4A shows that there were no significant differences in gambling persistence between experimental groups (p. > 0.05). Ghrelin concentrations after the gambling cues were the best predictor of gambling persistence regardless of experimental groups. Thus, the higher the ghrelin concentrations, the more likely subjects gambled in the face of continued loss (p. < 0.05).
predictors of persistent gambling in the face of continued loss in this experiment. While this was unexpected, it is likely that subjective gambling craving measures are more sensitive when used with pathological gamblers, a subgroup of individuals that were poorly represented in our sample. Alternatively, it is possible that the blood collection somewhat affected the way in which the participants responded to the questionnaires, somewhat inhibiting their self-reports of cravings, but not their actual behavioral responses. Nevertheless, and regardless of these potential discrepancies, ghrelin concentrations may actually be better predictors of gambling persistence and of potential for pathological gambling. Future studies should be conducted using pathological gamblers to determine if this is the case. Overall, our study represents the first attempt to examine the association between acyl ghrelin concentrations on gambling behavior under laboratory conditions that closely mimic a casino environment. Moreover, our data also supports previous pre-clinical data using the differential reinforcement of low rate task (DRL), a task where animals are only reinforced when the ratio between rewarded response and total responses is used to measure impulsive behaviors. Animals are considered more impulsive when they produce responses in spite of these not being reinforced, and therefore decreasing this ratio. In this study, rats infused with ghrelin into the ventricles or into the VTA had a lower DRL ratio, suggesting that these rats, like our subjects, were more likely to produce behavioral responses in spite of not being awarded a reinforcer (Anderberg et al., 2016). Similarly, our data is in line with recent study showing that fasting ghrelin concentrations in human experiment participants are associated not only with increased reward
ultimately resulted in average ghrelin concentrations that were about 25% higher than those seen in subjects in the other groups. Thus, while the fasting manipulation may not have worked as expected, it did seem to sensitize the ghrelin response to the gambling cue. This potentially could be mediated by increasing sympathetic tone that could increase interoceptive awareness of the gambling cues while also directly increasing ghrelin secretion (Herbert et al., 2012; Zhao et al., 2010) Given that the gambling cues increased plasma acyl ghrelin concentrations especially in fasted individuals, we expected that these individuals would also gamble the most in spite of persistent loss. Our results failed to support this. Nevertheless, and regardless of the experimental group, acyl ghrelin concentrations just prior to the gambling persistence test were the best predictor of continued gambling in the face of loss. This somewhat paradoxical effect might be related to the timing of the gambling persistence task in relation to the increases in ghrelin secretion following the gambling cue. As seen in Fig. 2, ghrelin concentrations peaked at 20 min after the presentation of the cue and remained higher in subjects that had been asked to fast overnight until the end of the study. Gambling behavior, however, was assessed in between these two time points. It is therefore likely that gambling behaviors in cued fasted subjects would have been higher than cued nonfasted participants if the testing had been conducted later in the experiment when the levels of ghrelin between these subjects were significantly different. Interestingly, while subjective measures of gambling cravings have been successfully validated as a reliable tool to predict gambling behavior (Wohl, Young, & Hart, 2007), ghrelin concentrations were better 120
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dopaminergic system, to be considered as potential targets for the treatment of behavioral addictions including gambling.
sensitivity, but also with increased scores in impulsivity measures (Ralevski et al., 2018). These results are also in line with data from studies linking novelty seeking and polymorphisms of the ghrelin receptor (Hansson et al., 2012). Interestingly, reward sensitivity, impulsivity and novelty seeking are traits highly associated with pathological gambling (Black et al., 2015; Goudriaan, Oosterlaan, de Beurs, & Van den Brink, 2004; Sztainert, Wohl, McManus, & Stead, 2014; Verdejo-Garcia, Lawrence, & Clark, 2008). There are, however, several limitations to this study that need to be acknowledged. For instance, and as mentioned above, our fasting protocol was not sufficient to increase ghrelin concentrations at the onset of the study. One could explain this as potential lack of compliance by some of the subjects, or that an overnight fast is not sufficient to increase ghrelin concentrations in human subjects. Nevertheless, fasted participants did show ghrelin concentrations that increased following the cue and that, in contrast to non-fasted participants, remained elevated until the end of the study. Perhaps the fasting protocol was not sufficient to increase basal ghrelin concentrations but sensitized ghrelin secretion in response to the gambling cues. Another limitation to our study was that we did not examine sex differences in our measures. The number of participants in this study, especially female participants, was not sufficient to allow for sex to be included as a variable. We do acknowledge this as a limitation, especially considering data clearly showing that gambling behavior is different in females vs males (Nower & Blaszczynski, 2006; van den Bos et al., 2013), and that, at least in preclinical studies, there are sex differences in the behavioral effects of ghrelin(Bagheri et al., 2015; Soriano-Guillen et al., 2016; Yamada et al., 2015). This is a topic currently being examined in our laboratory. Similarly, the number of subjects that could be considered problem gamblers was not sufficient to determine if this group would be a strong predictor of gambling persistence and of ghrelin secretion in response to cues, a limitation that is currently being considered for future studies. In addition to gambling, the secretion of ghrelin has been linked to increased motivation to obtain palatable foods, sex, alcohol, nicotine and other drugs of abuse in part through the stimulation of dopamine cells in the VTA (Abizaid, 2009; Perello & Dickson, 2015; Zallar, Farokhnia, Tunstall, Vendruscolo, & Leggio, 2017). Within the VTA, ghrelin stimulates dopamine cell activity, and the release of dopamine into a number of forebrain regions to facilitate reward seeking, contextual reward memories, and reinforcement (Chuang et al., 2011; Dickson et al., 2010; Hyland et al., 2018; Jerlhag et al., 2007; Kanoski, Fortin, Ricks, & Grill, 2013; King et al., 2011; Skibicka, Hansson, Alvarez-Crespo, Friberg, & Dickson, 2011; St-Onge et al., 2016; Wellman et al., 2012). Indeed, ghrelin intravenous injections to human participants enhanced the activity of brain centers associated with positive valence including the VTA and NAc, in response to images depicting palatable foods (Malik, McGlone, Bedrossian, & Dagher, 2008). Nevertheless, similar imaging studies where ghrelin is injected to gambling participants and using images associated with gambling have yet to be conducted. The present findings are compelling on a few fronts. First, they point to ghrelin as a potential target for a pharmacological treatment that reduces cravings produced by gambling associated cues in the same way that ghrelin and its receptor are currently targets to curb alcohol cravings (Leggio et al., 2014). For instance, ghrelin receptor antagonists may represent a means of reducing cravings in response to gambling cues in pathological gambling individuals. Findings also suggest that low cost preventive manipulations could be used to curb gambling and facilitate responsible gambling—manipulations like providing free or low cost food at a gambling venues to minimize the possibility that players are gambling on an empty stomach. More importantly, these data open the door to alternatives where metabolic signals like ghrelin and others like leptin and glucagon-like peptide 1 (GLP-1) (Hernandez et al., 2018; Kanoski, Hayes, & Skibicka, 2016; Schmidt et al., 2016; Shirazi, Dickson, & Skibicka, 2013), that also target the mesolimbic
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