D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement

Phase 2CompletedNCT02203786

Centre for Addiction and Mental Health60 enrolled

Overview

To determine if: 1. pathological gambling is similar to psychostimulant addiction as reflected by parallel roles for D1 and D2 receptors in gambling and stimulant reinforcement. 2. these parallel roles are linked with gambling pathology or if they are evident in both gamblers and controls.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

TRIPLE

Enrollment

Conditions

Pathological Gambling

Interventions

HaloperidolDRUG

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.

FluphenazineDRUG

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.

DexedrineDRUG

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.

Eligibility

Sex: ALLMin age: 19 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Centre for Addiction and Mental Health

Toronto, Ontario, Canada

Outcomes

Primary Outcomes

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.

Time frame: 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 Outcomes

Diastolic Blood Pressure (DBP)

Measure changes from baseline, especially physiologic reactivity to the slot machine and amphetamine.

Time frame: 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)

Time frame: At key points during testing: immediately after the slot machine, at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration)

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.