D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement

Study Overview
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Brief Summary
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To determine if: pathological gambling is similar to psychostimulant addiction as reflected by parallel roles for D1 and D2 receptors in gambling and stimulant reinforcement. these parallel roles are linked with gambling pathology or if they are evident in both gamblers and controls.

Detailed Description
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BACKGROUND: No previous research appears to have investigated the role of dopamine (DA) D1 or D2 receptors in psychostimulant reinforcement in pathological gamblers. Effects of haloperidol vs. placebo will reveal the role of D2 and the effects of fluphenazine vs. haloperidol will reveal the role of D1 in this process. OBJECTIVE: This study will begin to define the neurochemistry of Pathological Gambling by examining the roles of dopamine D1 and D2 receptors in gambling reinforcement and psychostimulant reinforcement, and exploring genetic predictors of response to DA probes in Pathological Gambling subjects (subjects) and healthy controls. METHODS: A double-blind, placebo controlled, counterbalanced between-within design will be employed. Each participant will attend 4 sessions with a minimum of 1 week between sessions to ensure drug washout. Responses to the slot machine will be assessed in sessions 1 and 2 (Phase I), and responses to amphetamine will be assessed in sessions 3 and 4 (Phase II). A second capsule (dummy) will be administered at expected peak levels for each antagonist on sessions 1 and 2 to standardize the procedure across sessions. Subjective reinforcement self-report scales will be administered at key intervals throughout the study. HYPOTHESIS: It is hypothesized that haloperidol (3-mg) will increase priming (Desire to Gamble, Gambling word salience) and pleasurable effects (e.g., Enjoyment/Liking) induced by playing a slot machine in Pathological Gambling subjects (N = 40). If gambling and stimulant reinforcement are mediated by common mechanisms, haloperidol will also increase priming and pleasurable effects of amphetamine (20-mg) in Pathological Gambling subjects. If D1 mediates effects of haloperidol, the mixed D1-D2 antagonist, fluphenazine (fluphenazine; 3-mg) will decrease or not alter responses to the slot machine and amphetamine in Pathological Gambling subjects. If D2 deficits are linked with gambling pathology, haloperidol will not affect slot machine or amphetamine reinforcement in controls (N= 40). If D1 deficits are linked with gambling pathology, fluphenazine will increase gambling and amphetamine reinforcement in controls, by mitigating undue D1 activation in subjects with high baseline D1 function. If D1 or D2 genes contribute to gambling or amphetamine reinforcement, genotype will predict responses to the manipulations.

Official Title
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Comparative Effects of a D2 and Mixed D1-D2 Dopamine Antagonist on Gambling and Amphetamine Reinforcement in Pathological Gamblers and Healthy Controls

Conditions
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Pathological Gambling

Intervention / Treatment
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* Drug: Haloperidol
* Drug: Fluphenazine
* Drug: Dexedrine
* Drug: Placebo
* Behavioral: Slot Machine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PATHOLOGICAL GAMBLERS otherwise healthy, non-treatment seeking, non-abstinent male or female ages 19-65 DSM-IV PG symptom scale score > 5 SOGS (South Oaks Gambling Screen) score > 5 nicotine dependence acceptable CONTROLS healthy male or female ages 19-65 DSM-IV PG symptom scale score = 0 SOGS score = 0 nicotine dependence acceptable must have played slot machine > 5 times Exclusion Criteria: both Pathological Gamblers and Controls Axis I psychopathology aside from nicotine dependence (or PG) based on SCID Schizotypal or Borderline Personality Disorder based on psychiatric interview Family history of schizophrenia or bipolar disorder English comprehension below grade 7 level. ADS (Alcohol Dependence Scale) > 13 (more than low dependence) BDI (Beck Depression Inventory) short form > 10 (more than low depression) DAST (Drug Abuse Screening Test) > 4 (possible drug abuse) Consumption of > 20/15 (men/women) standard alcoholic drinks/ week (hazardous drinking) Smoking > 20 cigarettes/day to help minimize withdrawal symptoms during test phase Any prior use of psychostimulant drugs Current use of medication that could interact with any of the study medications Women who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Haloperidol<br>Subjects randomized to pre-treatment drug sequence 1 (haloperidol on day 1 of each phase), or drug sequence 2 (haloperidol on day 2 of each phase). Dose 1: 3 visually identical capsules, each containing 1 mg haloperidol OR 3 visually identical placebo (lactose) capsules Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg dexedrine. Response measured to 15 min session of a commercial slot machine game. | Drug: Haloperidol<br>* Dose/maximum dose = 3-mg; route = oral. Participants assigned to the haloperidol antagonist group will receive 2 doses (@ 3 mg) on alternate sessions (with minimum of 2 weeks between individual doses). Dose 1: 3 visually identical capsules, each containing 1 mg haloperidol.<br>* Other names: Haldol;Drug: Dexedrine<br>* Dose/maximum dose = 20-mg; route = oral. All participants will receive 2 doses (@ 20 mg) during Phase II - sessions 3, 4, with minimum 1 week between individual doses. Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg D-amphetamine.<br>* Other names: D-amphetamine;Drug: Placebo<br>* Dose 1: On alternate sessions (1 and 3 or 2 and 4, depending on counterbalancing) participants will receive 3 visually identical placebo (lactose) capsules. Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1.<br>* Other names: lactose capsule;Behavioral: Slot Machine<br>* 15 minute play of a commercial slot machine game in bar-simulated laboratory setting.<br>* Other names: reward cue;|
| Active Comparator: Fluphenazine<br>Subjects randomized to pre-treatment drug sequence 1 (fluphenazine on day 1 of each phase), or drug sequence 2 (fluphenazine on day 2 of each phase). Dose 1: 3 visually identical capsules, each containing 1 mg fluphenazine OR 3 visually identical placebo (lactose) capsules Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg dexedrine. Response measured to 15 min session of a commercial slot machine game. | Drug: Fluphenazine<br>* Dose/maximum dose = 3-mg; route = oral. Participants assigned to the fluphenazine antagonist group will receive 2 doses (@ 3 mg) on alternate sessions (with minimum of 2 weeks between individual doses). Dose 1: 3 visually identical capsules, each containing 1 mg fluphenazine.<br>* Other names: Permitil;Drug: Dexedrine<br>* Dose/maximum dose = 20-mg; route = oral. All participants will receive 2 doses (@ 20 mg) during Phase II - sessions 3, 4, with minimum 1 week between individual doses. Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg D-amphetamine.<br>* Other names: D-amphetamine;Drug: Placebo<br>* Dose 1: On alternate sessions (1 and 3 or 2 and 4, depending on counterbalancing) participants will receive 3 visually identical placebo (lactose) capsules. Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1.<br>* Other names: lactose capsule;Behavioral: Slot Machine<br>* 15 minute play of a commercial slot machine game in bar-simulated laboratory setting.<br>* Other names: reward cue;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective Reinforcement Self-report Scales | Self-reported Confidence to Refrain from Gambling (0 - 10) was assessed at test session baseline, before the slot machine and after the slot machine (Phase 1); and before amphetamine and at peak amphetamine (Phase 2). The maximum score (10) denotes complete confidence to refrain from gambling (i.e., NO urge or compulsion to gamble); the minimum score (0) denotes complete lack of confidence to refrain from gambling (i.e., overwhelming urge to gamble). Scores between 10 and 0 denote intermediate confidence to refrain from gambling with LOWER scores denoting less confidence to refrain from gambling -- i.e., GREATER urge or compulsive motivation to gamble. Scores shown are based on single item visual analogue ratings 0-10 from each participant at the specified time point. The mean (SD) of these single item ratings is presented for each sub-group. | At key points in testing: immediately after the slot machine game, and at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diastolic Blood Pressure (DBP) | Measure changes from baseline, especially physiologic reactivity to the slot machine and amphetamine. | At key points in testing: immediately after the slot machine game (change from session baseline), and at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration)(change from session baseline). | 
| Cognitive Task Performance | Response time to words (gambling, alcohol, positive affect, negative affect) as a percentage of neutral categorized words (parts of a building). This provides an index of the relative salience of stimuli from these four categories against a baseline of reaction to words with no clinical relevance or emotional valence. Smaller scores indicate faster relative response time to the test stimuli vs. neutral stimuli (i.e., greater salience) | At key points during testing: immediately after the slot machine, at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration) | 
| Betting Behaviour in Laboratory-based Slot Machine Game | Risk taking was operationally defined as credits wagered per spin (mean computed for total spins) | 1x per test session (total of 4 test sessions) for duration of the study: 4 weeks (1 session/week) | 
| Speed of Play on Slot Machine Game | Number of individual spins in a 15-minute slot machine game. Each spin corresponds to one wager. | 15-minutes | 
| Winnings on Slot Machine Upon Completion of Game | Credits | 15-minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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amphetamine, d1 and d2 receptors, dopamine antagonists, pathological gambling, priming, reinforcement