Martin Zack

Opioid and dopamine mediation of gambling responses in recreational gamblers

Stress, cues, and pharmacological priming are linked with relapse to addictive behavior. Increased salience and decreased inhibitory control are thought to mediate the effects of relapse-related stimuli. However, the functional relationship between these two processes is unclear. To address this issue, a modified Stop Signal Task was employed, which used Alcohol, Neutral, and Non-Words as Go stimuli, and lexical decision as the Go response. Subjects were 38 male problem drinkers (mean Alcohol Dependence Scale (ADS) score: 18.0). Uncontrollable noise (~10 min at 110 dB) was the stressor; nonalcoholic placebo beer (P-Beer) was the cue manipulation, and alcohol (0.7 g/kg), the pharmacological prime. Half the sample received alcohol, and half P-Beer. Stress and beverage (test drink vs soft drink) were manipulated within subjects on two sessions, with half the sample receiving active manipulations together and half receiving them separately. Go response time (RT) and Stop Signal RT (SSRT) were slower to Alcohol than Neutral words. Stress augmented this bias. Alcohol and P-Beer impaired overall SSRT. Stress impaired neither overall SSRT nor Go RT. SSRT to Neutral words and Non-Words correlated inversely with Go RT to Alcohol and Neutral words, and Non-Words. ADS correlated directly with SSRT to Alcohol words. A resource allocation account was proposed, whereby diversion of limited resources to salient cues effectively yoked otherwise independent Go and Stop processes. Disturbances of prefrontal norepinephrine and dopamine were cited as possibly accounting for these effects. Treatments that optimize prefrontal catecholamine transmission may deter relapse by reducing disinhibitory effects of salient eliciting stimuli.

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.

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 Parkinsons 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.

Pathological gambling (PG) is a serious psychiatric disorder afflicting 1-3% of the general population. Experimental evidence indicates shared neurochemical substrates for PG and psychostimulant addiction. Impulsivity characterizes one key subtype of PG. Therefore, medications that ameliorate psychostimulant addiction and impulsive syndromes might also benefit impulsive PG subjects. The atypical stimulant, modafinil reduces cocaine abuse and impulsivity in patients with ADHD. The present study sought to determine if modafinil (200 mg) would reduce the reinforcing effects of slot machine gambling in PG subjects, and if this effect was stronger in high (H-I) vs. low (L-I) impulsivity subjects (N = 20). A placebo-controlled, double-blind, counterbalanced, repeated measures design was employed. Apart from bet size, which declined uniformly in both groups under drug, modafinil had bi-directional effects in the two groups. In H-I subjects, the drug decreased desire to gamble, salience of Gambling words, disinhibition and risky decision-making. In L-I subjects, modafinil increased scores on these indices. Modafinil also differentially affected blood pressure response to the game in the two groups. These findings for modafinil appear to fit well with a growing literature demonstrating bi-directional effects of D2 agonists as a function of trait impulsivity. Impulsivity could critically moderate medication response in PG.

Background: This study tested the appraisal disruption hypothesis of alcohol stress response dampening (SRD) in male and female high or low anxiety sensitive (AS) undergraduates. The hypothesis predicts that alcohol SRD will be greater when drinking occurs before versus after stress exposure. High AS males' predominant social‐evaluative concerns further implied that alcohol SRD to a social stressor (i.e., a speech) would be relatively stronger in high AS males than in high AS females.Methods: Male and female (n=90/gender) high and low AS participants (≥70th; ≤30th percentile on Anxiety Sensitivity Index‐Revised) were matched on drinking habits and randomly assigned to 1 of 9 experimental cells. Drink type—alcohol (0.7 g/kg males; 0.63 g/kg females), placebo, soda—was fully crossed with stress condition—drink before stress (DBS), drink after stress (DAS), and no stress control (NSC). Stress was induced by telling participants they would be required to make a self‐revealing speech. Stress response dampening was assessed for state anxiety on the Spielberger scale and Stroop interference to threat‐related words. Subjective desire for alcohol was also assessed.Results: Relative to placebo, alcohol (peak blood alcohol concentration, 0.064%) reliably reduced state anxiety in high AS but not in low AS participants. Alcohol decreased STAI scores and Stroop interference to social threat words significantly more in the DBS than the DAS condition in high AS males; high AS females displayed the exact opposite pattern of effects. In contrast to other participants, high AS males also reported relatively strong desire scores under alcohol.Conclusions: Overall, the results do not support the appraisal disruption hypothesis as a general mechanism of alcohol SRD in undergraduate drinkers. The findings for high AS males do support the hypothesis, while the opposing profile for high AS females implies that the nature of the stressor (i.e., social challenge) may contribute to gender differences in alcohol SRD in high AS individuals.

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.