1. Investigating Dopamine Function in Pathological Gambling with [11C]Raclopride and [11C]-(+)-PHNO PET
Doris Payer, Isabelle Boileau, Martin Zack, et al.
Centre for Addiction and Mental Health, Toronto, ON, Canada
Society of Biological Psychiatry 67th Annual Scientific Convention
Oral Session #4, Friday, May 4, 2012

2. disclosures
None of the authors have any conflicts of interest to disclose.
Funding for this study was provided by the Ontario Problem Gambling Research Centre (MZ, IB) and the Canadian Institutes of Health Research (IB)

3. PATHOLOGICAL GAMBLING
Compulsive gambling behaviour that interferes with personal and social health
Shares clinical, phenomenological, diagnostic, epidemiological features with SUD
Similar progression: recreational practice  pathology
High comorbidity (2-10 fold higher rate of SUD in PG)
Genetic commonalities (TaqA1 allele of the DRD2)
Diagnostic criteria:
DSM-5: Reclassification from “ICD not elsewhere categorized” to “Addiction and Related Disorders” – But neurochemical parallels not fully understood.

4. Focus on dopamine system
Central role in reward and reinforcement
Focus of many addiction/SUD studies
DA D2 levels ↓
Stimulant/opiate addiction, food/internet ‘addiction’
DA D3 (expressed in limbic areas: reward/motivation) ↑
Preclinical models, postmortem human brain, PET study of MA abuse
DA release ↑ in animals (sensitization), ↓ in humans (reward deficiency)

5. Dopamine in pg Few studies, findings not conclusive
CSF metabolites, gene polymorphisms, pharmacological modulation  DA involved
Small number of neuroimaging studies focused on DA
fMRI: VS activation ↓ (Reuter)
PET: Striatal D2/3 receptor levels no different, DA release ↑ (PD patients with PG and ICD), associated with gambling excitement and severity (Steeves, O’Sullivan, Linnet, Joutsa)
This study
Resting baseline
[11C]-(+)-PHNO -- measures D3 where expressed (ventral > dorsal striatum, substantia nigra (Tziortzi)), more sensitive to displacement (Shotbolt))

6. STUDY Aims & Hypotheses
Study 1: Is there a difference in D2/D3 receptor binding between PG and HC?
Measure resting baseline DA D2/D3
[11C]Raclopride (D2/D3): expect PG < HC
[11C](+)PHNO (D3): expect PG > HC (D3-expressing regions)
Study 2: Is there a difference in DA transmission between PG and HC?
Measure DA release following amphetamine challenge (0.4mg/kg oral)
Change in [11C](+)PHNO binding: expect PG > HC (sensitization)

7. Participants & Design Inclusion/Exclusion Outcome Measures
PG Group (N=13)
Male
DSM-IV Dx for PG
SOGS > 11 (cutoff for PG)
Non-treatment-seeking
HC Group (N=12)
No DSM-IV Dx
SOGS = 0
All subjects
Drug/medication free (except some alcohol, nicotine, light marijuana)
Stimulant-naïve
Mentally and physically healthy
Outcome Measures
Self-report questionnaires
Gambling episode (out of scanner, 15 min of actual slot machine play)
[11C]Raclopride PET
[11C]PHNO PET: pre-, post- amphetamine (0.4mg/kg oral, 2hrs pre-scan)
MRI for coregistration

8. Participant characteristics
PG (N=13)
HC (N=12)
Age
32.5 ±8.5
33.8 ±11.2
Education
15.2 ±1.6
15.9 ±0.5
Number of smokers 4 3
BDI Score*
5.4 ± 4.9
0.8 ± 1.4
Eysenck Impulsiveness*
4.2 ± 1.6
2.8 ± 1.3
SOGS Score*
11.7 ±3.5
0.0 ± 0.0
Gambler’s Beliefs Questionnaire*
72.5 ±25.9
117.0 ±22.2
GBQ Luck/ Perseverance*
49.9 ±18.4
77.3 ±9.7
GBQ Illusion of Control*
22.6 ±8.4
39.7 ±13.0
$ spent gambling per week*
±240.37
1.08 ±1.68
% of income spent gambling*
28.9 ±20.6
0.18 ±0.38
Impulsiveness and Gambling Beliefs predict Gambling Severity
Eysenck Impulsiveness correlation with
SOGS (r=.72, p=.005)
DSM-IV-based Questionnaire (r=.75, p=.003)
Gambler’s Beliefs Questionnaire correlation with
SOGS (Luck/Perseverance r=-.57, p=.042; Total r=-.47, p=.10)
DSM-IV-based Questionnaire (Luck/Perseverance r=-.59, p=.036; Total (r=-.57, p = .04)

9. GAMBLING EPISODE: SUBJECTIVE RESPONSES
Slot-machine game
No significant group differences in performance (rate of play, bet per spin)
Subjective responses: PG > HC on all subscales (all p < .01)
Reinforcing properties: PG > HC self- reported “Desire to Gamble” (p < .001), PG < HC “Confidence in Ability to Resist Gambling” (p < .001)

10. PET measures (baseline)
[11C]Raclopride
[11C]-(+)-PHNO
-10% PG HC PG HC
No significant difference between groups in any of the ROIs (incl. SN PHNO)
BUT, trends in dorsal putamen and anterior dorsal caudate (within range observed in SUD)

11. Relationships between substantia nigra binding (d3) and gambling / impulsivity

12. Relationships between substantia nigra binding (d3) and gambling / impulsivity
Reminiscent of findings in SUD

13. Study 2 - DA release (PHNO displacement)
0.4mg/kg dexedrine (oral amphetamine), 2nd PHNO Scan (120 min post)
Relative decrease in binding ( = DA release) in both groups in all ROIs
Greater DA release in PG than HC – evidence for sensitization
50% greater in caudate, 70% greater in putamen PG HC

14. Study 2 - AMPHETAMINE CHALLENGE
Found expected subjective/physiological amphetamine effects, but in both groups
Physiological effects: HR, BP, cortisol ↑
Subjective effects: energy ↑, amphetamine/ benzedrine/euphoria (ARCI) ↑, sedation ↓
Gambling-reinforcing effects: desire to gamble ↑, ability to resist gambling ↓
Mood: POMS Vigor-Activity, Tension-Anxiety ↑, Fatigue- Inertia ↓
No measure showed differential effect between PG and HC

15. Relationship between da release and gambling severity
SOGS Score
PHNO Displacement in Ventral Striatum
r = -.563, p = .056
Relationship between % displacement (more negative = more DA release) in ventral striatum and gambling severity in PG

16. STUDY Summary
No significant abnormalities in PG in baseline D2 receptor binding (in line with raclopride PET studies)
D3 receptor levels not higher in PG, but related to gambling severity and impulsiveness (// Meth/Cocaine abuse)
Amphetamine decreased [11C](+)PHNO binding (DA release)
Displacement greater in PG – evidence for dopaminergic sensitization (In line with previous PET studies of PG (Steeves, O’Sullivan)
Amphetamine had expected subjective/physiological effects
No interaction with group– i.e.: no behavioural sensitization
DA release related to gambling severity (in line with Joutsa)
Greater DA release (at D3 receptors) may increase risk for PG

17. Conclusions & IMPLICATIONS
Results at odds with SUD
But, may inform understanding of both PG and SUD:
SUD might be progression from phase involving sensitization to compulsive drive toward treating DA deficiency
SUD findings may be confounded by supra- physiological effects of drugs on DA system (e.g., neurotoxicity/adaptations)
Present findings may represent model of addicted state in the absence of such effects

18. Thank you!! Funding sources CAMH Colleagues & Collaborators
Isabelle Boileau, PhD
Martin Zack, PhD
Bindiya Chugani, MSc
Stephen J. Kish, PhD
Arian Behzadi, MD
Tina McCluskey, MSc
Sylvain Houle, MD
Pablo M. Rusjan, PhD
Alan A. Wilson, PhD
Tony P. George, MD
Funding sources
OPGRC
CIHR
Research participants
Your attention!