Neuroimaging of reward mechanisms in Gambling disorder: an integrative review.

Gambling disorder (GD) was reclassified as a behavioral addiction in the DSM-5 and shares clinical and behavioral features with substance use disorders (SUDs). Neuroimaging studies of GD hold promise in isolating core features of the addiction syndrome, avoiding confounding effects of drug neurotoxicity. At the same time, a neurobiologically-grounded theory of how behaviors like gambling can become addictive remains lacking, posing a significant hurdle for ongoing decisions in addiction nosology. This article integrates research on reward-related brain activity (functional MRI) and neurotransmitter function (PET) in GD, alongside the consideration of structural MRI data as to whether these signals more likely reflect pre-existing vulnerability or neuroadaptive change. Where possible, we point to qualitative similarities and differences with established markers for SUDs. Structural MRI studies indicate modest changes in regional gray matter volume and diffuse reductions in white matter integrity in GD, contrasting with clear structural deterioration in SUDs. Functional MRI studies consistently identify dysregulation in reward-related circuitry (primarily ventral striatum and medial prefrontal cortex), but evidence is mixed as to the direction of these effects. The need for further parsing of reward sub-processes is emphasized, including anticipation vs outcome, gains vs. losses, and disorder-relevant cues vs natural rewards. Neurotransmitter PET studies indicate amplified dopamine (DA) release in GD, in the context of minimal differences in baseline DA D2 receptor binding, highlighting a distinct profile from SUDs. Preliminary work has investigated further contributions of opioids, GABA and serotonin. Neuroimaging data increasingly highlight divergent profiles in GD vs. SUDs. The ability of gambling to perpetually activate DA (via maximal uncertainty) may contribute to neuroimaging similarities between GD and SUDs, whereas the supra-physiological DA effects of drugs may partly explain differences in the neuroimaging profile of the two syndromes. Coupled with consistent observations of correlations with gambling severity and related clinical variables within GD samples, the overall pattern of effects is interpreted as a likely combination of shared vulnerability markers across GD and SUDs, but with further experience-dependent neuroadaptive processes in GD.

How uncertainty begets hope: A model of adaptive and maladaptive seeking behavior.

The "incentive hope" model creatively explains hoarding and fat accumulation by foragers under uncertainty and food seeking when food cues are present but food is not. The model has difficulty explaining why animals driven by cues fare better than animals driven by food reward itself, why human obesity exists when food is abundant, and why people enjoy gambling and care about winning.

Uncertainty exposure causes behavioural sensitization and increases risky decision-making in male rats: toward modelling gambling disorder.

BACKGROUND: An animal model of gambling disorder, previously known as pathological gambling, could advance our understanding of the disorder and help with treatment development. We hypothesized that repeated exposure to uncertainty during gambling induces behavioural and dopamine (DA) sensitization - similar to chronic exposure to drugs of abuse. Uncertainty exposure (UE) may also increase risky decision-making in an animal model of gambling disorder. METHODS: Male Sprague Dawley rats received 56 UE sessions, during which animals responded for saccharin according to an unpredictable, variable ratio schedule of reinforcement (VR group). Control animals responded on a predictable, fixed ratio schedule (FR group). Rats yoked to receive unpredictable reward were also included (Y group). Animals were then tested on the Rat Gambling Task (rGT), an analogue of the Iowa Gambling Task, to measure decision-making. RESULTS: Compared with the FR group, the VR and Y groups experienced a greater locomotor response following administration of amphetamine. On the rGT, the FR and Y groups preferred the advantageous options over the risky, disadvantageous options throughout testing (40 sessions). However, rats in the VR group did not have a significant preference for the advantageous options during sessions 20-40. Amphetamine had a small, but significant, effect on decision-making only in the VR group. After rGT testing, only the VR group showed greater hyperactivity following administration of amphetamine compared with the FR group. LIMITATIONS: Reward uncertainty was the only gambling feature modelled. CONCLUSION: Actively responding for uncertain reward likely sensitized the DA system and impaired the ability to make optimal decisions, modelling some aspects of gambling disorder.

[¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved.

Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.

Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

Engineered highs: Reward variability and frequency as potential prerequisites of behavioural addiction.

Influential learning-based accounts of substance addictions posit the attribution of incentive salience to drug-associated cues, and its escalation by the direct dopaminergic effects of drugs. In translating this account to disordered gambling, we have noted how the intermittent nature of monetary rewards in gambling (i.e. the variable ratio) may allow for analogous learning processes, via effects on dopaminergic signalling. The aim of the present article is to consider how multiple sources of reward variability operate within modern gambling products, and how similar sources of variability, as well as some novel sources of variability, also apply to other digital products implicated in behavioural addictions, including gaming, shopping, social media and online pornography. Online access to these activities facilitates not only unparalleled accessibility but also introduces novel forms of reward variability, as seen in the effects of infinite scrolls and personalized recommendations. We use the term uncertainty to refer to the subjective experience of reward variability. We further highlight two psychological factors that appear to moderate the effects of uncertainty: 1) the timecourse of uncertainty, especially with regard to its resolution, 2) the frequency of exposure, allowing temporal compression. Collectively, the evidence illustrates how qualitative and quantitative variability of reward can confer addictive potential to non-drug reinforcers by exploiting the psychological and neural processes that rely on predictability to guide reward seeking behaviour.

Association of cannabis use with neurocognition in adolescents with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) and cannabis use are each associated with neurocognitive deficits in adolescents. However, little is known regarding the association of neurocognition with cannabis use among adolescents with BD. Therefore, we examined this topic in a sample of adolescents with BD and healthy control (HC) adolescents. METHODS: Participants included 121 adolescents (n = 32 with BD and lifetime cannabis use (BDCB+), n = 31 with BD and no lifetime cannabis use (BDCB-), n = 58 HC with no lifetime cannabis use), aged 14-20 years. Five neurocognitive subtests of the computerized CANTAB battery were assessed. Groups were compared using an analysis of covariance (ANCOVA) covarying for age, sex, and intelligence quotient. RESULTS: The three groups differed significantly on tests of visuospatial working memory (F = 4.41, p = 0.014, ηp2=0.07) and sustained attention (F = 5.15, p = 0.007, ηp2=0.08). Post hoc analyses revealed working memory scores were significantly worse in BDCB+ versus HC (p = 0.04, d = 0.59), and sustained attention was significantly worse in BDCB- versus HC (p = 0.006, d = 0.70). CONCLUSION: These preliminary findings suggest that cannabis use among adolescents with BD is associated with working memory deficits. Future studies in larger samples are warranted to evaluate causation versus predisposition to cannabis use, and to evaluate duration, quantity, and potency of cannabis on neurocognition among adolescents with BD.

Priming effects of a slot machine game and amphetamine on probabilistic risk-taking in people with gambling disorder and healthy controls.

INTRODUCTION: The Game of Dice Task (GDT) captures probabilistic risk-taking, which is an important feature of addictions and integral to gambling disorder (GD). No research appears to have assessed effects of gambling-specific priming manipulations or the pharmacological basis of such effects on the GDT. AIMS: To investigate effects of slot machine gambling (Slots) and d-amphetamine (AMPH; 20 mg) on risk-taking in people with GD and healthy controls (HCs) (n = 30/group). The role of dopamine (DA) was assessed by pre-treating participants with the D2 receptor (D2R)-preferring antagonist, haloperidol (HAL; 3-mg) or mixed D1R-D2R antagonist, fluphenazine (FLU; 3-mg). HYPOTHESES: Slots and AMPH will each increase risk-taking based on fewer (less probable) possible outcomes selected (POS) and poorer net monetary outcomes (NMO; gains minus losses) on the GDT, with stronger effects in Group GD. If DA mediates these effects, outcomes will vary with pre-treatment. METHOD: Participants attended a pre-experimental baseline session and 4 test sessions. Antagonist Group (HAL, FLU) was manipulated between-participants. Pre-treatment (antagonist, placebo) was manipulated within-participants and counterbalanced over sessions for Slots and AMPH test phases. Moderator/mediator effects of trait and neuropsychological factors and GD severity (South Oaks Gambling Screen; SOGS) were explored via covariance. RESULTS: AMPH led to an escalation in risky POS over trial blocks in both groups, regardless of pre-treatment. Cognitive inflexibility (high perseveration-proneness) moderated this effect in Group HC. In Group GD, SOGS selectively predicted riskier POS on AMPH sessions. Group GD achieved poorer NMO vs. Group HC on the pre-experimental baseline and Placebo-Slots sessions. Group HC selectively displayed poorer NMO on the Antagonist-Slots session. CONCLUSIONS: The GDT can detect behavioral and pharmacological priming effects. Cognitive inflexibility and symptom severity moderate AMPH-induced risk-taking in HC and GD participants, respectively. Sensitization-related "wanting" of risk may contribute to the latter effect in people with GD.

Haloperidol modifies instrumental aspects of slot machine gambling in pathological gamblers and healthy controls.

Instrumental conditioning has been implicated in persistence at slot machine gambling, but its specific role remains unclear. Dopamine (DA) mediates aspects of instrumental responding, and D2 antagonists reliably alter this process. This study investigated the effects of the preferential D2 antagonist, haloperidol (3 mg) on reward-related betting behavior in 20 subjects with pathological gambling (PG) and 18 healthy controls. Hierarchical regression assessed the prospective relationship between Payoff and Bet Size on consecutive trials, along with potential moderating effects of Cumulative Winnings and Phase of game (early/late) under drug and placebo. Payoff predicted Bet Size on the next trial regardless of other factors, consistent with an instrumental view of slot machine gambling. Under placebo, this correlation varied as a function of Winnings and Phase in PG subjects but was strong and invariant in Controls. Under haloperidol, the Payoff-Bet Size correlation in PG subjects resembled the invariant pattern of Controls under placebo. In contrast, the Payoff-Bet Size correlation rose then fell sharply over trials under haloperidol in controls. The correlation of Payoff with Bet Size is remarkable given that there is no actual contingency between winning and betting, and suggests that reward expectancies largely drive slot machine gambling. By blocking inhibitory D2 receptors, haloperidol may have reversed 'tolerance' to monetary reward mediated by increased tonic DA in PG subjects. Disturbance of the Payoff-Bet Size correlation in controls may reflect indiscriminate reward signaling under haloperidol in subjects with normal DA function. Indirect enhancement of DA transmission may reduce undue reward-related responding in PG subjects.

Dopaminergic signaling of uncertainty and the aetiology of gambling addiction.

Although there is increasing clinical recognition of behavioral addictions, of which gambling disorder is the prototype example, there is a limited understanding of the psychological properties of (non-substance-related) behaviors that enable them to become 'addictive' in a way that is comparable to drugs of abuse. According to an influential application of reinforcement learning to substance addictions, the direct effects of drugs to release dopamine can create a perpetual escalation of incentive salience. This article focusses on reward uncertainty, which is proposed to be the core feature of gambling that creates the capacity for addiction. We describe the neuro-dynamics of the dopamine response to uncertainty that may allow a similar escalation of incentive salience, and its relevance to behavioral addictions. We review translational evidence from both preclinical animal models and human clinical research, including studies in people with gambling disorder. Further, we describe the evidence for 1) the effects of the omission of expected reward as a stressor and to promote sensitization, 2) the effect of the resolution of reward uncertainty as a source of value, 3) structural characteristics of modern Electronic Gaming Machines (EGMs) in leveraging these mechanisms, 4) analogies to the aberrant salience hypothesis of psychosis for creating and maintaining gambling-related cognitive distortions. This neurobiologically-inspired model has implications for harm profiling of other putative behavioral addictions, as well as offering avenues for enhancing neurological, pharmacological and psychological treatments for gambling disorder, and harm reduction strategies for EGM design.

Effects of exposure to chronic uncertainty and a sensitizing regimen of amphetamine injections on locomotion, decision-making, and dopamine receptors in rats.

Gambling disorder (GD) is a behavioral addiction that may be linked to alterations in dopamine (DA) systems. Gambling involves chronic exposure to uncertain reward, which can sensitize the activity of DA systems. Here we explored how combinations of Pavlovian and instrumental uncertainty impact DA sensitization and risky decision-making. Experiment 1: 40 rats underwent 66 uncertainty exposure (UE) sessions during which they responded for saccharin. Animal responding was reinforced according to a fixed or variable (FR/VR) ratio schedule that turned on a conditioned stimulus (CS; light), which predicted saccharin on 50% or 100% of trials. Animals responded under one of the four conditions: FR-CS100% (no uncertainty), VR-CS100%, FR-CS50%, and VR-CS50% (maximal uncertainty). DA sensitization was inferred from an enhanced locomotor response to d-amphetamine (d-AMPH; 0.5 mg/kg) challenge. The rat gambling task (rGT) was used to assess decision-making. Experiment 2: 24 rats received 5 weeks of sensitizing d-AMPH or saline doses, followed by locomotor activity and rGT testing. Experiment 3: Effects of UE and a sensitizing d-AMPH regimen on DA D1, D2, and D3 receptor binding were assessed in 44 rats using autoradiography. Compared to FR-CS100%, VR-CS100% and VR-CS50% rats displayed a greater locomotor response to d-AMPH, and VR-CS50% rats demonstrated riskier decision-making. Chronic d-AMPH-treated rats mirrored the effects of VR-CS50% groups on these two indices. Both VR-CS50% and d-AMPH-treated groups had increased striatal DA D2 receptor binding. These results suggest that chronic uncertainty exposure, similar to exposure to a sensitizing d-AMPH regimen, sensitized the function of DA systems and increased risky decision-making.

Prevalence of Fetal Alcohol Exposure by Analysis of Meconium Fatty Acid Ethyl Esters; A National Canadian Study.

Our study aimed to estimate the prevalence of heavy fetal alcohol exposure through the analysis of meconium FAEEs as an objective biomarker of fetal exposure. We conducted a study on meconium samples collected nationwide through the Maternal-Infant Research on Environmental Chemicals (MIREC) Study Group. FAEE in meconium was quantified by an established headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (SPME GC-MS). Out of 1315 samples collected in 10 Canadian obstetric units coast to coast between 2008-2011, the estimated prevalence of positive meconium FAEE ranged between 1.16% and 2.40%, translating into at least 1800 new cases of FASD in Canada each year. Positive maternal self- reports of heavy alcohol use were tenfold lower (0.24%). Use of meconium FAEE revealed tenfold more cases of heavy exposure to maternal drinking than did maternal reports. The use of objective measures of maternal alcohol exposure is critical in accurately estimating risks and in monitoring effective prevention of FASD.

Impulsivity moderates the effects of dopamine D2 and mixed D1-D2 antagonists in individuals with gambling disorder.

BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.

Development and psychometric evaluation of a three-dimensional Gambling Motives Questionnaire.

AIMS: This study was designed to develop and evaluate a self-report measure of gambling motives. Participants A community-recruited sample of 193 gamblers (70% male; mean age = 35.5 years) were selected to fill two groups according to scores on the South Oaks Gambling Screen: probable pathological gamblers (PPG; n = 154) and non-pathological gamblers (NPG; n = 39). MEASURES: Participants completed a novel 15-item measure of gambling motives called the Gambling Motives Questionnaire (GMQ), which was modeled after the original Drinking Motives Questionnaire, as well as a variety of gambling behavior and problem criterion measures. RESULTS: An exploratory principal components analysis revealed three intercorrelated factors tapping enhancement (ENH), coping (COP), and social (SOC) motives, respectively. Each GMQ subscale showed good internal consistency (alphas > 0.80). The PPG group scored higher on all three scales than the NPG group, with larger differences for ENH and COP. In line with the clinical literature, PPG women scored higher than PPG men on the COP subscale but also, unexpectedly, on the SOC subscale. In concurrent validity analyses, ENH consistently predicted greater gambling behavior, and COP and ENH consistently predicted more severe gambling problems. With gambling behavior levels controlled, only COP remained a significant predictor of gambling problem severity. Finally, gender interacted with gambling motives in predicting gambling problem severity: COP predicted gambling problems more strongly in women, whereas ENH predicted gambling problems more strongly in men. CONCLUSIONS: The GMQ appears to be a promising tool for both research and clinical applications with problem gamblers.

Subtyping pathological gamblers on the basis of affective motivations for gambling: relations to gambling problems, drinking problems, and affective motivations for drinking.

Pathological gamblers who drink when gambling (n=158; 77% men; mean age=36.0 years) completed the Inventory of Gambling Situations (IGS) and gambling and drinking criterion measures. Principal components analysis on the IGS subscales revealed negative (e.g., Unpleasant Emotions) and positive (e.g., Pleasant Emotions) gambling situation factors. Subjecting IGS factor scores to cluster analysis revealed three clusters: (a) enhancement gamblers, with low negative and high positive factor scores; (b) coping gamblers, with very high negative and high positive factor scores; and (c) low emotion regulation gamblers, with low negative and positive factor scores (59%, 23%, and 18% of the sample, respectively). Clusters were validated with a direct measure of gambling motives. Additional validity analyses showed that coping gamblers scored higher than the other groups on a variety of different gambling activities, gambling problems, drinking frequency, drinking problems, and coping drinking motives, whereas low emotion regulation gamblers scored lower than the other groups on gambling frequency, gambling problems, drinking quantity, and enhancement drinking motives. The findings validate this empirical approach to subtyping gamblers and suggest consistency of motives across addictive behaviors.

A D2 antagonist enhances the rewarding and priming effects of a gambling episode in pathological gamblers.

Previous research indicated shared neurochemical substrates for gambling and psychostimulant reward. This suggests that dopamine substrates may directly govern the reinforcement process in pathological gambling. To investigate this issue, the present study assessed the effects of the relatively selective dopamine D2 antagonist, haloperidol (3 mg, oral) on responses to actual gambling (15 min on a slot machine) in 20 non-comorbid pathological gamblers and 18 non-gambler controls in a placebo-controlled, double-blind, counterbalanced design. In gamblers, haloperidol significantly increased self-reported rewarding effects of gambling, post-game priming of desire to gamble, facilitation of reading speed to Gambling words, and gambling-induced elevation in blood pressure. In controls, haloperidol augmented gambling-induced elevation in blood pressure, but had no effect on other indices. The findings provide direct experimental evidence that the D2 substrate modulates gambling reinforcement in pathological gamblers.

Parallel role for the dopamine D1 receptor in gambling and amphetamine reinforcement in healthy volunteers.

This study investigated the role of dopamine, and specifically the D1 receptor (D1R), in the reinforcing effects of a slot-machine game in healthy volunteers ( n=30). To compare gambling and drug effects, subjects received the prototypic psychostimulant drug d-amphetamine (AMPH; 20 mg) in a multi-session, placebo-controlled design. To isolate D1R, half the subjects were pretreated with the preferential D2 receptor antagonist haloperidol (HAL; 3 mg), and the other half with the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg) before the game (Phase I) and AMPH (Phase II). HAL decreased and FLU increased the post-game desire to gamble and post-AMPH desire to take AMPH again, as well as amphetamine scale ratings on the Addiction Research Center Inventory after gambling and AMPH. The effects of the antagonists on desire to gamble and to take AMPH again were significantly intercorrelated. HAL increased and FLU decreased the salience of negative affective words on a rapid reading task after both reinforcers. HAL also decreased the salience of gambling words after AMPH. Both reinforcers increased diastolic blood pressure equally under antagonists and placebo. Results indicate that D1R plays a parallel role in the psychostimulant-like, incentive-motivational, and salience-enhancing effects of gambling and AMPH. Moderate D1R activation appears to optimize these effects in healthy subjects.

Negative affect words prime beer consumption in young drinkers.

Negative affect is consistently associated with pathological aspects of alcohol use. Priming of motivation for alcohol by negative affect cues may contribute to this relationship. This study sought to determine whether: (a) exposure to negative affect words primes actual drinking behavior; (b) this effect is related to severity of alcohol problems; and (c) these effects are moderated by gender and anxiety sensitivity. Prime words (negative, positive, neutral) were administered using a synonym generation task. Primed drinking behavior was measured in a taste-test procedure, using placebo beer. Drinking scores were significantly greater in the negative affect condition than in the other two conditions, which did not differ from each other. Problem drinking severity directly predicted priming effects of negative affect words but was unrelated to drinking in the other two word prime conditions. Anxiety sensitivity was unrelated to drinking in any condition. Even unobtrusive exposure to negative affect cues can prime drinking behavior in young drinkers, and this effect is tied to the severity of alcohol problems.

Effects of High Frequency Repeated Transcranial Magnetic Stimulation and Continuous Theta Burst Stimulation on Gambling Reinforcement, Delay Discounting, and Stroop Interference in Men with Pathological Gambling.

BACKGROUND: Repeated transcranial magnetic stimulation (rTMS) can reduce cravings and improve cognitive function in substance dependent individuals. Whether these benefits extend to individuals with pathological gambling (PG) is unclear. High-frequency rTMS of the medial prefrontal cortex (PFC) and continuous theta burst stimulation (cTBS) of the right dorsolateral PFC can reduce impulsive choice in healthy volunteers. OBJECTIVE: This study aimed to assess the effects of these two protocols on gambling reinforcement and related responses in otherwise healthy men with PG. METHODS: Participants (n = 9) underwent active or sham treatments at weekly intervals in a repeated-measures, Latin square design. Subjective and physiological responses were assessed before and after a 15-min slot machine game on each session. Delay discounting and Stroop tasks measured post-game impulsive choice and attentional control. RESULTS: Multivariate analysis of covariance, controlling for winnings on the slot machine under each treatment, found that rTMS reduced the post-game increase in Desire to Gamble; cTBS reduced amphetamine-like effects, and decreased diastolic blood pressure. Treatment had no significant univariate effects on bet size or speed of play in the game; however, a multivariate effect for the two indices suggested that treatment decreased behavioral activation. Neither treatment reduced impulsive choice, while both treatments increased Stroop interference. CONCLUSIONS: rTMS and cTBS can reduce gambling reinforcement in non-comorbid men with PG. Separate processes appear to mediate gambling reinforcement and betting behavior as against delay discounting and Stroop interference. Interventions that modify risky as opposed to temporal aspects of decision making may better predict therapeutic response in PG.