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

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)

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.

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)

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))

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)

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

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* 197.69 ±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)

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)

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)

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

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

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

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

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

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

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

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!