Dopamine mediates a directionally opposite correlation between empathy and the reinforcing effects of amphetamine and gambling in people with gambling disorder vs. healthy controls.

Understanding the relationship between empathy, subjective effects of addictive reinforcers and dopamine function in people with gambling disorder (PGD) vs. healthy controls (HCs) may inform GD treatment. The current investigation addressed this issue via retrospective analysis of data from three studies using amphetamine and a slot machine (SLOTS) as reinforcers in PGD and HCs. The Empathy scale of Eysenck's Impulsiveness Questionnaire assessed trait Empathy. The Gamblers Beliefs Questionnaire assessed cognitive distortions. The Eysenck Lie scale assessed socially desirable responding. PET scans quantified dopamine receptor expression and amphetamine-induced dopamine release in Study 1. Pre-treatment with the D2-receptor (D2R)-preferring antagonist, haloperidol or D1R-D2R antagonist, fluphenazine before SLOTS tested the role of D2 autoreceptors and post-synaptic D2R in Study 2. Pre-treatment with the multi-system indirect dopamine agonist, modafinil before SLOTS assessed the reliability of correlations in PGD. Striatal D2R expression predicted greater Empathy and lower amphetamine 'Liking' in HCs, and predicted greater symptom severity in PGD. Empathy predicted lower 'Exciting' effects of SLOTS under placebo in HCs; no correlation emerged under either antagonist. Relative to placebo, haloperidol decreased, whereas fluphenazine increased, the positive correlation between Empathy and Exciting effects of SLOTS in PGD. Modafinil markedly reduced the positive correlation between Empathy and Exciting effects of SLOTS seen under placebo in PGD. Empathy predicted greater cognitive distortions in PGD in all studies. Lie scale variance influenced several primary effects. Prior research linking the insula with Empathy, reactivity to interoceptive signals for risky rewards (uncertainty), and cognitive distortions, provides a parsimonious account for these results.

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.

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.

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.