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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., Competing Interests: Declaration of competing interest None of the authors declares a conflict of interest in the report of the findings in this manuscript. There was no use of Artificial Intelligence or any AI application in the preparation of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A variety of evidence suggests important commonalities in the neurochemical basis of reinforcement in pathological gambling (PG) and psychostimulant addiction. This article focuses on the parallel and specific roles that dopamine (DA) activation plays in these two disorders, beyond its generic role in reinforcement. A psychostimulant-mimetic model for PG is proposed based on evidence from the following domains: Acute subjective-behavioral effects of gambling and psychostimulants; Effects of anticipated rewards and uncertainty of reward delivery (key elements of gambling) on DA release; Relationship between DA release and positive arousal; Cross-priming of motivation for gambling by amphetamine; Effects of DA D2 antagonists on gambling and amphetamine reward; Effects of mixed D1-D2 antagonists on clinical symptoms of PG; Effects of DA D2 agonists on experimental measures of risk-taking, gambling, and induction of PG in patients with Parkinson's disease; Electrophysiological and cognitive disturbances associated with chronic exposure to gambling and psychostimulants, and the possible role of sensitization in these effects. Limitations of the model regarding the exclusive role of DA are discussed with particular reference to genetic risk, co-morbidity, and sub-types of PG. Suggestions for future research include isolating the roles of DA receptor subtypes in PG, and parallel within-subject assessment of DA manipulations on gambling and psychostimulant reinforcement in PG subjects and controls.

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.Neuropsychopharmacology (2007) 32, 1678–1686; doi:10.1038/sj.npp.1301295; published online 3 January 2007 [ABSTRACT FROM AUTHOR]

Abstract: This study examined the effects of modafinil (200 mg) on slot machine betting profiles from a previous sample of low and high impulsivity (LI/HI) pathological gamblers (10/Group; Zack and Poulos, 2009). Hierarchical regression assessed the prospective relationship between Payoff and Bet Size on consecutive trials, along with moderating effects of Group, Cumulative Winnings (low/high) and Phase of game (early/late) under drug and placebo. Y intercepts for the simple regressions of Bet Size on Payoff indexed overall motivation to bet. Under placebo, both groups gauged their bets less closely to the preceding Payoff as trials continued when Winnings were low but not high. Under modafinil, both groups gauged their bets more closely to the preceding Payoff when Winnings were low but gauged their bets less closely to the previous Payoff when Winnings were high. The tendency to gauge bets closely to the previous Payoff coincided with a bias toward low overall Bet Size, and modafinil accentuated this relationship, in LI but not HI subjects. Results suggest that modafinil increases the salience of environmental rewards, leading to more tightly calibrated responses to individual rewards when resources are low, but progressively loosens reward-response calibration when resources are high. Increased relative impact of phasic vs. tonic dopamine signals may account for patterns seen at low vs. high Winnings, respectively, under the drug. Clinically, modafinil may deter pathological gamblers from chasing losses but also encourage them to continue betting rather than quit while they are ahead. Whether low-dose modafinil confers more uniform benefits deserves investigation. [Copyright &y& Elsevier]