DOES THE D 3 DOPAMINE RECEPTOR (D 3 r)play A ROLE IN ADDICTION? Isabelle Boileau, PhD

DOES THE D 3 DOPAMINE RECEPTOR (D 3 r)play A ROLE IN ADDICTION? Isabelle Boileau, PhD

Acknowledgments Human Neurochemical Pathology Lab Stephen J. Kish, PhD Jun Chao Tong, PhD Centre for Movement Disorders Mark Guttman, MD John Adams, MD Alanna Sheinberg Jill Burkeholder Vivian M. Rakoff PET Imaging Centre Sylvain Houle, MD Alan Wilson, PhD Pablo Rusjan, PhD Alvina Ng Jeannie Fong Armando Garcia Winston Stableford Min Wong Tina McCluske Funding: CIHR, OMHF

Overview Investigating the role of the DA D 3 receptor in humans - D 3 in Addiction / Impulse control disorder (ICD) PART I The D 3 r system: What is special about it? PART II D 2 and D 3 r levels are differentially affected by changes in DA levels PART III Rational that the D 3 r could be involved in addiction PART IV Preliminary data on the D 3 r in stimulant users PART V Status of the D 3 r in patients with PD who gamble

What is special about the D 3 R? D 2 mrna D 3 D 2 (and D 1 ): pharmacology, transduction system & ANATOMY Overall the D 3 out numbered by the D 2 (2X) D 2 : High expression in whole striatum (mesocortical system) D 3 mrna D 3 : lower expression DC /DP D 3: high expression in ventral (limbic) striatum, Island of Calleja, septum and nucleus basalis (mesolimbic system)

The D 3 Limbic Localization: Cognitive / Motivational / Emotional Function? D 2 binding D 3 binding Caudate / Putamen Caudate / Putamen Ventral Striatum Ventral Striatum Joyce, 1994

Elusive Role of the D 3 The role of the D 3 r in humans remains largely elusive Lack of research tools (Radioligands, Antibodie, Specific pharmacological agents, Knock-out mice) Possible to study D 3 r binding in humans in vivo with PET

Investigating D 3 with PET ABT-925 baseline ABT-925 50-150mg ABT-925 600mg DS BP ND 4 GP BP ND 0 Midbrain Narendran, 2007 Graff-Guerrero, 2009 (+)[ 11 C]PHNO a full D 2/3 receptor agonist PET tracer and a D 3 preferring ligand Bio-distribution is consistent with D 3 in humans Binding blocked by D 3 antagonist

D 3 vs. D 2 response to Changes in DA levels D 3 vs. D 2 respond differently to DA depletion COMPLETELY counters the concept of denervation supersensitivity

D 2 is UP in PD! Increased [ 11 C]Raclopride in PD (Rinne, 1995) Increased [H 3 }Sulipride in MPTP treated monkey (Graham, 1990)

Diaz, 1995 Paradoxically D 3 is DOWN!

Q.: Do striatal D 3 r in human behave the same way as they do in animal studies chronically depleted of DA? STUDY I Objective: to compare D 3 vs D 2 binding in drug-naïve PD and controls Hypothesis: D 2 r ([ 11 C]raclopride binding) = UP-REGULATED in never treated patients with PD; D 3 r ([ 11 C](+)PHNO binding) = DOWN REGULATED.

PD patients have DECREASED D 3 binding and INCREASED D 2 binding Subjects: 10 de-novo PD 10 controls Scans with [ 11 C]raclopride and [ 11 C](+)PHNO 28% 14% 26%

t-maps

D 3 r level is increased after repeated DAergic stimulation D 2 and the D 1 r D 3 r is after repeated DAergic stimulation Related to Sensitization to DA agonist Guillin 2001

Sensitization: model of addiction Repeated DAergic stimulation = greater sensitivity to the effects of the drug (motor activity); response to cues associated with a rewarding response

Repeated DAergic stimulation Leads to an OVER EXPRESSION of D 3 * * * *mrna Bordet, 1997 Related to BEHAVIORAL SENSITIZATION

Changes also Occur in the Dorsal Striatum! Bordet, 1997 REMARKABLE ectopic up regulation!!

D 3 a plausible candidate for Stimulant addiction? D 3 = density in limbic regions D 3 after DAergic stimulation D 3 antagonist rewarding/reinforcing actions of drugs / natural reward ICSS of reward areas cue-induced cocaine SA stress-triggered cocaine-seeking cocaine and heroin-induced CPP alcohol intake and seeking in rats and mice nicotine-triggered nicotine seeking cue-triggered sucrose seeking D 3 in cocaine overdose fatalities

AIM of the Study D 3 r plays a role in stimulant addiction? There are no in vivo data on status of the D 3 system in addiction Goal: measure levels of D 3 in brain of poly stimulant users during early abstinence (min.14 days) Hypothesis: D 3 levels ([ 11 C](+)PHNO binding) are in stimulant users

Experimental Design METH confirmed in hair analysis Negative urine on scan day

Sub.Nigra Volkow Martinez Unlike the finding for D 2, D 3 does not appear to be 6.00 CTRL MA 5.50 5.00 20% 4.50 4.00 3.50 3.00 2.50 [ 11 C]-(+)-PHNO 2.00 1.50 1.00 9% 36% D.Caudate D.Putamen V.Striatum V.Pallidum G.Pallidus

Correlation /Regression Q.: is [ 11 C](+)PHNO binding related to DFS 70.00 60.00 Drug use severity 50.00 Craving 40.00 physiological / subjective 30.00 responses to a priming dose of 20.00 amphetamine (0.4mg/kg) 10.00 negative withdrawal state AST Calm 70.00 65.00 60.00 55.00 50.00 45.00 40.00 35.00 AST LST SMST sn mood / cognition / motor fct 30.00 0.00 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 PHNO BP 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 PHNO BP 12.00 10.00 sn Linear (sn) 12.00 10.00 AST LST SMST 8.00 8.00 Want 6.00 Years Meth use 6.00 4.00 4.00 2.00 2.00 0.00 0.00 0.50 1.00 1.50 2.00 2.50 3.00 PHNO BP 0.00 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 PHNO BP

Summary D 3 receptor levels in (+Meth / COC) users binding was related to drug related wanting, anxiety / mind-racing and self-reported craving binding in striatal (DC) areas were related to years of use Does this mean that there is no decrease in D2? PHNO binding in dorsal striatum is mostly to D 2 : our finding suggest that Users might not be sever enough Decreased D 2 was masked by an ectopic upregulation of D 3 receptors

Q.: Can changes in D 3 r levels explain sensitization to DA replacement therapy in PD Q.: Is the occurrence of ICD (i.e.: sensitization) in PD related to D 3

Impulse Control Disorders In PD ICD: failure to resist an impulse, drive, or temptation to perform an act that is harmful to the person or others. Manifestations include Craving and Compulsive use of PD medication Pathological Gambling Hyper Sexuality Compulsive Shopping Binge Eating Punding / Hobbyism

Are D 3 Preferring Agonists Related to ICD?

Objective: to compare D 3 ((+)[ 11 C] PHNO) to D 2 (([ 11 C] raclopride) in PD with ICD relative to de novo PD We expected D 2 to be DOWN and D 3 to be UP!

Is D 3 UP in PD with ICD? SUBJECTS: Age:61; 4M, 2F;PD duration: 8 years, UPDRS 24, Peg Board 9; SOGS: 16, DSM: 13, GA20: 13 4.50 Control (n = 9) DeNovo (n = 10) Gamblers (n = 6) 4.00 3.50 P = 0.02 P = 0.04 3.00 [ 11 C] BPND 2.50 2.00 1.50 1.00 0.50 0.00 PHNO GP PHNO Striatum Raclopride Striatum

Overall Summary DA Depletion: Differential change in D 2 and D 3 DA stimulation with meds or drugs of abuse: might increase D 3 D 3 D 2 D 2 D 3

Future Questions / Conclusion Representative sample: Does D 3 = vulnerability factor for addiction / ICD? Addiction pharmacotherapies targeting the D 3 may be more viable: localization of D 3 primarily in limbic areas reinforcing effects of drugs with less motoric side effects Preliminary data in line with the rational for testing D 3 receptor blockade as anti-craving agents