C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention The Dopamine D 3 Receptor System: New Possibilities for Dopamine-Based Reward Christian A. Heidbreder, Ph.D.

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Selective Dopamine D 3 Antagonists: Commitment to Target for Drug Abuse (I) Distribution: –Contrary to DA D 1 and D 2 receptors, DA D 3 receptors are expressed preferentially in granule cells of the islands of Calleja and in medium-sized spiny neurons of the rostral and ventromedial shell of the NAc, regions in which the D 2 receptors are scarcely expressed ( Gurevitch and Joyce, 1999 ) –The distribution of the D 3 receptor in the human brain appears to follow a rather similar pattern to that observed in the rat brain ( Hall et al., 1996; Shafer and Levant, 1998; Suzuki et al., 1998; Gurevich and Joyce, 1999 )

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Dopamine D 3 Antagonists: Commitment to Target for Drug Dependence (II) Expression in disease tissues: –The density of DA D 3 receptors is elevated one-to-threefold in the NAc and ventromedial subregions of the caudate-putamen in the brains of cocaine overdose fatalities ( Staley and Mash, 1996; Mash and Staley, 1999 ) –The expression of DA D 3 receptor mRNA in the human NAc is increased six-fold in cocaine overdose victims ( Segal et al., 1997 )

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Dopamine D 3 Antagonists: Commitment to Target for Drug Dependence (III) Expression in disease models: –Termination of a cocaine self-administration regimen increases DA D 3 binding over time (Neisewander et al., 2004) –D 3 mRNA and receptors are increased in cocaine cue-conditioned locomotion (Le Foll et al., 2002) –Nicotine-induced conditioned locomotion and nicotine-induced behavioural sensitisation are associated with significant increases in D 3 receptor binding and mRNA levels in the shell subregion of the NAc (Le Foll et al., 2003) –Sub-chronic exposure to morphine was shown to produce a significant increase in D 3 receptor mRNA in the caudate-putamen and ventral midbrain, including the substantia nigra and VTA (Spangler et al., 2003)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Why has the Role of DA D 3 Receptors in Drug Addiction been Hampered so far? Lack of pharmacological tools showing significant selectivity for DA D 3 over DA D 2 receptors Most compounds used in animal models of drug addiction have a 10- to 30-fold selectivity for DA D 3 over D 2 receptors in vivo: AJ76: 2-6 DS 121: 4 UH 232: 4-8 Nafadotride: 6-9 U99194: S14297: 23-61

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Target Validation with Tool Compound 100 fold selective for hD 3 over hD 2 in radioligand binding assays Potent, competitive D 3 receptor antagonist (pKb 8.4, 80 fold functional selectivity over hD 2 ) 100 fold selective over 66 other receptors, ion channels and enzymes Lacks agonist activity at hD 2 and hD 3 receptors No effects on spontaneous locomotor activity (2-42 mg/kg p.o.) No effects on open field exploration (3-51mg/kg p.o.) Non-cataleptogenic up to 80 mg/kg p.o. No elevation of plasma prolactin at 93 mg/kg p.o. No proconvulsant effects up to 93 mg/kg p.o. SB A N N H N O NC

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Efficacy Against Nicotine Dependence

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Nicotine-Triggered Relapse to Nicotine-Seeking Andreoli et al. (2003)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Nicotine Cue-Conditioned Hyperlocomotor Activity N N H N O NC SB Pilla et al. (2004)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Nicotine- Induced Conditioned Place Preference N N H N O NC SB PAIRED (min) UNPAIRED (min) A A: Veh/Veh/Veh B B: Veh/Nico/Veh CDE C: Veh/Nico/1mgD: Veh/Nico/3mgE: Veh/Nico/10mg ? ? Vehicle Nicotine Test Ashby et al. (2004)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Nicotine Enhancement of Brain Stimulation Reward * Campos et al. (2003) N N H N O NC SB Frequency (Hz) Log Scale Lever Presses/30 sec

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Efficacy Against Cocaine Dependence

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Cocaine-Triggered Relapse to Cocaine-Seeking Extinction Prime + Veh Prime + SB 3 mg/kgPrime + SB 6 mg/kg Prime + SB 12 mg/kg Non-rewarded lever presses Cocaine seeking * ** Vorel et al. (2003) N N H N O NC SB

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention SB A Dose-Dependently Reduces Cocaine-Related Cue-Induced Relapse to Cocaine Seeking Cervo et al. (2003) N N H N O NC SB

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Cocaine Self-administration under a 2 nd Order Schedule of Reinforcement Di Ciano et al. (2003)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A on Cocaine-Induced Conditioned Place Preference * SB277011A can block the acquisition of cocaine-induced CPP * * SB277011A can block the expression of cocaine-induced CPP Vorel et al. (2003)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention SB A Inhibits Cocaine SA Behavior under FR-10 Reinforcement (Representative cocaine infusions, 3 hrs) Vehicle + Cocaine (0.5 mg/kg, FR10) SB + Cocaine (0.5 mg/kg, FR10) Infusions / 3 hrs Vehicle SB A (24 mg/kg) (Mean +/- S.E.M.) Cocaine (mg/kg/infusion) *** * Xi et al. (2004) SB A (mg/kg, i.p.) Time (min) to 20 Lever Presses Cocaine (0.75 mg/kg/infusion)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention SB A Inhibits Cocaine SA Behavior under PR Reinforcement SB A (mg/kg) Veh61224 Break-Point * *** Xi et al. (2004)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of SB A (3-12 mg/kg i.p.) on Stress-Triggered Relapse to Cocaine-Seeking Xi et al. (2003)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Effect of Intracerebral Administration of SB A on Stress-Triggered Relapse to Cocaine-Seeking Xi et al. (2003)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Why are the Effects Observed with SB A D 3 - rather than D 2 - mediated? (I) In contrast with DA D 2 antagonists, SB A does not produce any significant effect on spontaneous locomotion; In contrast with DA D 2 receptor antagonists, SB A is not cataleptogenic at doses up to 78.8 mg/kg; In contrast with DA D 2 receptor antagonists, SB A does not increase serum prolactin levels (hyperprolactinaemia); SB A can reverse the DA D 3 preferring agonist quinelorane- induced decrease in extracellular DA levels in the NAc. In contrast, the effects of quinelorane in the dorsal striatum are not reversed even by doses of SB A up to 93 mg/kg, thus further reflecting regional differences in DA D 3 receptor regulation of DA outflow;

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Why are the Effects Observed with SB A D 3 - rather than D 2 - mediated? (II) In contrast with DA D 2 antagonists, SB A does not produce a significant right-shift along the pulse frequency axis in the rate-frequency curve paradigm of the intracranial self-stimulation behavior; SB A does not produce conditioned place aversion in contrast with both the DA D 3 agonists 7-OH-DPAT and PD and the partial D 3 agonist BP-897; SB A does not alter nicotine or cocaine self-administration under an FR-1 schedule of reinforcement SB A does not alter natural reinforcers: sucrose (2 nd order schedule and oral ethanol self-administration, food self-administration, and food CPP.

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Why Selective DA D 3 Receptor Antagonists Might be Promising for the treatment of Drug Addiction? Higher efficacy than gold standards Immediate effect No side effects or drop outs due to adverse/aversive effects No abuse liability No tolerance to efficacy following long-term treatment Treatment of multiple dependencies (nicotine, alcohol, cocaine, heroin) Potential of treatment of psychiatric co-morbidities (e.g. schizophrenia)

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention Acknowledgements Dr. Eliot L. Gardner, NIDA/NIH, Baltimore, USA Dr. Charles R. Ashby, Saint John’s University, New York, USA Prof. Barry J. Everitt, University of Cambridge, UK Dr. Luigi Cervo, Mario Negri Research Institute, Milano, Italy Dr. Peter K. Thanos, Brookhaven National Labs, Upton, New York, USA Drs Maria Pilla, Michela Andreoli, Michela Tessari, Dan Hutcheson