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Selective Dopamine D 3 Antagonists: Commitment to Target for Drug Abuse (I)

The Dopamine D 3 Receptor System: New Possibilities for Dopamine-Based Reward Christian A. Heidbreder, Ph.D. Selective Dopamine D 3 Antagonists: Commitment to Target for Drug Abuse (I). Distribution:

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Selective Dopamine D 3 Antagonists: Commitment to Target for Drug Abuse (I)

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  1. The Dopamine D3 Receptor System:New Possibilities for Dopamine-Based RewardChristian A. Heidbreder, Ph.D.

  2. Selective Dopamine D3 Antagonists:Commitment to Target for Drug Abuse (I) • Distribution: • Contrary to DA D1 and D2 receptors, DA D3 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 D2 receptors are scarcely expressed (Gurevitch and Joyce, 1999) • The distribution of the D3 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)

  3. Dopamine D3 Antagonists:Commitment to Target for Drug Dependence (II) • Expression in disease tissues: • The density of DA D3 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 D3 receptor mRNA in the human NAc is increased six-fold in cocaine overdose victims (Segal et al., 1997)

  4. Dopamine D3 Antagonists:Commitment to Target for Drug Dependence (III) • Expression in disease models: • Termination of a cocaine self-administration regimen increases DA D3 binding over time (Neisewander et al., 2004) • D3 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 D3 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 D3 receptor mRNA in the caudate-putamen and ventral midbrain, including the substantia nigra and VTA (Spangler et al., 2003)

  5. Why has the Role of DA D3 Receptorsin Drug Addiction been Hampered so far? • Lack of pharmacological tools showing significant selectivity for DA D3 over DA D2 receptors • Most compounds used in animal models of drug addiction have a 10- to 30-fold selectivity for DA D3 over D2 receptors in vivo: • AJ76: 2-6 • DS 121: 4 • UH 232: 4-8 • Nafadotride: 6-9 • U99194: 10-14 • S14297: 23-61

  6. N H N O N N C Target Validation with Tool Compound SB-277011-A • 100 fold selective for hD3 over hD2 in radioligand binding assays • Potent, competitive D3 receptor antagonist (pKb 8.4, 80 fold functional selectivity over hD2) • 100 fold selective over 66 other receptors, ion channels and enzymes • Lacks agonist activity at hD2 and hD3 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.

  7. Efficacy Against Nicotine Dependence

  8. Veh/Sal Saline vs. Nicotine Veh/Nic 250 011-3/Nic 011-10/Nic 200 ** ** 150 Cumulative nicotine-paired lever presses * 100 ** * * * * 50 ** 0 30 60 90 120 Session duration (min) Effect of SB-277011-A on Nicotine-TriggeredRelapse to Nicotine-Seeking Andreoli et al. (2003)

  9. N H N O N N C SB-277011 Effect of SB-277011-A on NicotineCue-Conditioned Hyperlocomotor Activity Pilla et al. (2004)

  10. N H N O N 12 Vehicle N C SB-277011 9 Nicotine 6 3 ? ? Test PAIRED (min) UNPAIRED (min) 0 A B C D E A: Veh/Veh/Veh B: Veh/Nico/Veh C: Veh/Nico/1mg D: Veh/Nico/3mg E: Veh/Nico/10mg Effect of SB-277011-A on Nicotine-Induced Conditioned Place Preference Ashby et al. (2004)

  11. N H N O N N C SB-277011 Lever Presses/30 sec * Frequency (Hz) Log Scale Effect of SB-277011-A on Nicotine Enhancement of Brain Stimulation Reward Campos et al. (2003)

  12. Efficacy Against Cocaine Dependence

  13. N H N O 50 N N C SB-277011 40 30 * Non-rewarded lever presses Cocaine seeking ** 20 10 0 Extinction Prime + Veh Prime + SB 3 mg/kg Prime + SB 6 mg/kg Prime + SB 12 mg/kg Effect of SB-277011-A on Cocaine-TriggeredRelapse to Cocaine-Seeking Vorel et al. (2003)

  14. N Self- H Extinction Reinstatement N administration Cocaine & cues Cocaine associated-cues O N Saline & cues Saline associated-cues 40 § N C SB-277011 Saline-associated Vehicle cues 30 § Vehicle Active lever SB 277011-A 3 mg/kg 20 Cocaine-associated cues SB 277011-A 10 mg/kg * SB 277011-A 30 mg/kg 10 * 10 20 30 40 50 60 0 Number of responses 0 Saline-associated Vehicle cues 10 Vehicle Inactive lever SB 277011-A 3 mg/kg Cocaine-associated cues SB 277011-A 10 mg/kg 0 0 0 3 10 30 SB 277011-A 30 mg/kg Last three Last three days days 0 10 20 30 40 50 60 SB-277011-A, mg/kg, i.p. SB-277011-A Dose-Dependently ReducesCocaine-Related Cue-Induced Relapse to Cocaine Seeking Cervo et al. (2003)

  15. Second Interval First Interval 300 250 250 200 200 * 150 * * 150 # of Responses 100 * 100 * 50 50 0 0 Active Lever veh 0.3 3 10 20 30 veh 0.3 3 10 20 30 60 60 50 50 40 40 30 30 # of Inactive Responses 20 20 10 10 0 0 veh 0.3 3 10 20 30 veh 0.3 3 10 20 30 Inactive Lever Dose of SB-277011-A Dose of SB-277011-A Effect of SB-277011-A on Cocaine Self-administrationunder a 2nd Order Schedule of Reinforcement Di Ciano et al. (2003)

  16. * SB277011A can block the acquisition of cocaine-induced CPP * * SB277011A can block the expression of cocaine-induced CPP Effect of SB-277011-A on Cocaine-InducedConditioned Place Preference Vorel et al. (2003)

  17. (Representative cocaine infusions, 3 hrs) Vehicle + Cocaine (0.5 mg/kg, FR10) Cocaine (0.75 mg/kg/infusion) 140 SB + Cocaine (0.5 mg/kg, FR10) 120 100 80 Time (min) to 20 Lever Presses 60 40 20 0 100 Vehicle 0 3 6 12 24 SB-277011A (mg/kg, i.p.) SB-277011A (24 mg/kg) 80 60 Infusions / 3 hrs * 40 *** 20 (Mean +/- S.E.M.) 0 0.125 0.25 0.5 Cocaine (mg/kg/infusion) SB-277011-A Inhibits Cocaine SA Behaviorunder FR-10 Reinforcement Xi et al. (2004)

  18. After Vehicle After SB-277011A (24 mg/kg) 800 80 } Break-Point =145 600 60 400 Cumulative Lever Presses } Break-Point =15 40 Cumulative Lever Presses 200 20 0 Cocaine = 0.5 mg/kg/infusion 0 Cocaine = 0.5 mg/kg/infusion 0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200 Time (min) Time (min) 120 100 * 80 Break-Point 60 *** 40 20 0 Veh 6 12 24 SB-277011A (mg/kg) SB-277011-A Inhibits Cocaine SA Behaviorunder PR Reinforcement Xi et al. (2004)

  19. Effect of SB-277011-A (3-12 mg/kg i.p.) onStress-Triggered Relapse to Cocaine-Seeking Xi et al. (2003)

  20. Effect of Intracerebral Administration of SB-277011-Aon Stress-Triggered Relapse to Cocaine-Seeking Xi et al. (2003)

  21. Why are the Effects Observed with SB-277011-AD3- rather than D2- mediated? (I) • In contrast with DA D2 antagonists, SB-277011-A does not produce any significant effect on spontaneous locomotion; • In contrast with DA D2 receptor antagonists, SB-277011-A is not cataleptogenic at doses up to 78.8 mg/kg; • In contrast with DA D2 receptor antagonists, SB-277011-A does not increase serum prolactin levels (hyperprolactinaemia); • SB-277011-A can reverse the DA D3 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-277011-A up to 93 mg/kg, thus further reflecting regional differences in DA D3 receptor regulation of DA outflow;

  22. Why are the Effects Observed with SB-277011-AD3- rather than D2- mediated? (II) • In contrast with DA D2 antagonists, SB-277011-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-277011-A does not produce conditioned place aversion in contrast with both the DA D3 agonists 7-OH-DPAT and PD-128907 and the partial D3 agonist BP-897; • SB-277011-A does not alter nicotine or cocaine self-administration under an FR-1 schedule of reinforcement • SB-277011-A does not alter natural reinforcers: sucrose (2nd order schedule and oral ethanol self-administration, food self-administration, and food CPP.

  23. Why Selective DA D3 Receptor AntagonistsMight 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)

  24. 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

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