D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement
Condition: Pathological Gambling
MeSH terms: Gambling
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Haloperidol; Fluphenazine; Dexedrine; Placebo; Slot Machine
Intervention type(s): Drug; Drug; Drug; Drug; Behavioral
Intervention description(s): 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.; 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.; 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.; 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.; 15 minute play of a commercial slot machine game in bar-simulated laboratory setting.
Other intervention name(s): Teva-Haloperidol; DIN: 00396818; Haldol; APO-Fluphenazine; DIN: 00405345; Prolixin; Permitil; Dextro-amphetamine sulphate; DIN: 01924516; D-amphetamine; lactose capsule; reward cue
Intervention MeSH terms: Haloperidol; Haloperidol decanoate; Fluphenazine; Fluphenazine depot; Fluphenazine enanthate; Amphetamine; Dextroamphetamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: amphetamine; d1 and d2 receptors; dopamine antagonists; pathological gambling; priming; reinforcement