D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement (HFDEX)

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

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.

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.

amphetamine, d1 and d2 receptors, dopamine antagonists, pathological gambling, priming, reinforcement

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.

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.

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.

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).

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).

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)

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

APA (2000) Diagnostic and Statistical Manual of Mental Disorders. IV-TR ed. American Psychiatric Association: Washington, DC.

Enggasser JL, de Wit H. Haloperidol reduces stimulant and reinforcing effects of ethanol in social drinkers. Alcohol Clin Exp Res. 2001 Oct;25(10):1448-56.

Holley FO, Magliozzi JR, Stanski DR, Lombrozo L, Hollister LE. Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol Ther. 1983 Apr;33(4):477-84. doi: 10.1038/clpt.1983.65.

Lesieur HR, Blume SB. The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers. Am J Psychiatry. 1987 Sep;144(9):1184-8. doi: 10.1176/ajp.144.9.1184.

Midha KK, McKay G, Edom R, Korchinski ED, Hawes EM, Hall K. Kinetics of oral fluphenazine disposition in humans by GC-MS. Eur J Clin Pharmacol. 1983;25(5):709-11. doi: 10.1007/BF00542363.

Wachtel SR, Ortengren A, de Wit H. The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers. Drug Alcohol Depend. 2002 Sep 1;68(1):23-33. doi: 10.1016/s0376-8716(02)00104-7.

Wong YN, Wang L, Hartman L, Simcoe D, Chen Y, Laughton W, Eldon R, Markland C, Grebow P. Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers. J Clin Pharmacol. 1998 Oct;38(10):971-8. doi: 10.1002/j.1552-4604.1998.tb04395.x.

The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.