D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement

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.

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