The Dopamine D3 Receptor System: New Possibilities for Dopamine-Based Reward Christian A. Heidbreder, Ph. D. Selective Dopamine D3 Antagonists: Commitment to Target for Drug Abuse (I)


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


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)


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)


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)


Why has the Role of DA D3 Receptors in 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


Target Validation with Tool Compound



Efficacy Against Nicotine Dependence



Effect of SB-277011-A on Nicotine-Triggered Relapse to Nicotine-Seeking



Effect of SB-277011-A on Nicotine Cue-Conditioned Hyperlocomotor Activity



Effect of SB-277011-A on Nicotine- Induced Conditioned Place Preference





Efficacy Against Cocaine Dependence



Effect of SB-277011-A on Cocaine-Triggered Relapse to Cocaine-Seeking



SB-277011-A Dose-Dependently Reduces Cocaine-Related Cue-Induced Relapse to Cocaine Seeking



Effect of SB-277011-A on Cocaine Self-administration under a 2nd Order Schedule of Reinforcement



Effect of SB-277011-A on Cocaine-Induced Conditioned Place Preference



SB-277011-A Inhibits Cocaine SA Behavior under FR-10 Reinforcement



SB-277011-A Inhibits Cocaine SA Behavior under PR Reinforcement



Effect of SB-277011-A (3-12 mg/kg i.p.) on Stress-Triggered Relapse to Cocaine-Seeking



Effect of Intracerebral Administration of SB-277011-A on Stress-Triggered Relapse to Cocaine-Seeking



Why are the Effects Observed with SB-277011-A D3- 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;



Why are the Effects Observed with SB-277011-A D3- 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.



Why Selective DA D3 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)



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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