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Research ArticleNeuropharmacology

In Vivo Occupancy of Dopamine D3 Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder

V. Barth, A. B. Need, E. T. Tzavara, B. Giros, C. Overshiner, S. D. Gleason, M. Wade, A. M. Johansson, K. Perry, G. G. Nomikos and J. M. Witkin
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 501-510; DOI: https://doi.org/10.1124/jpet.112.198895
V. Barth
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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A. B. Need
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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E. T. Tzavara
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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B. Giros
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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C. Overshiner
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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S. D. Gleason
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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M. Wade
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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A. M. Johansson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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K. Perry
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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G. G. Nomikos
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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J. M. Witkin
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (V.B., A.B.N., C.O., S.D.G., M.W., A.M.J., K.P., G.G.N., J.M.W.); and INSERM U-952, Université Pierre et Marie Curie, Paris, France (E.T.T., B.G.)
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Abstract

Dopamine D3 receptors have eluded definitive linkage to neurologic and psychiatric disorders since their cloning over 20 years ago. We report a new method that does not employ a radiolabel for simultaneously defining in vivo receptor occupancy of D3 and D2 receptors in rat brain after systemic dosing using the tracer epidepride (N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-5-iodo-2,3-dimethoxybenzamide). Decreases in epidepride binding in lobule 9 of cerebellum (rich in D3 receptors) were compared with nonspecific binding in the lateral cerebellum. The in vivo occupancy of the dopamine D3 receptors was dose dependently increased by SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide) and U99194 (2,3-dihydro-5,6-dimethoxy- N,N-dipropyl-1H-inden-2-amine). Both antagonists increased extracellular levels of acetylcholine (ACh) in the medial prefrontal cortex of rats and modified brain-tissue levels of ACh and choline. Consistent with these findings, the D3 receptor antagonists enhanced the acquisition of learning of rats either alone or in the presence of the norepinephrine uptake blocker reboxetine as with the attention-deficit–hyperactivity disorder (ADHD) drug methylphenidate. Like reboxetine, the D3 receptor antagonists also prevented deficits induced by scopolamine in object recognition memory of rats. Mice in which the dopamine transporter (DAT) has been deleted exhibit hyperactivity that is normalized by compounds that are effective in the treatment of ADHD. Both D3 receptor antagonists decreased the hyperactivity of DAT−/− mice without affecting the activity of wild type controls. The present findings indicate that dopamine D3 receptor antagonists engender cognition-enhancing and hyperactivity-dampening effects. Thus, D3 receptor blockade could be considered as a novel treatment approach for cognitive deficits and hyperactivity syndromes, including those observed in ADHD.

Footnotes

  • A portion of the data presented was previously presented in abstract form at the following conference: J. M. Witkin, S. D. Gleason, C. Overshiner, M. R. Wade, K. A. Svensson, K. Perry, B. Giros, E. T. Tzavara, and G. G. Nomikos (2005) In vivo occupancy of dopamine D3 receptors by antagonists produces neurochemical and behavioral effects of potential relevance to attention-deficit-hyperactivity-disorder. American College of Neuropsychopharmacology; 2005 Dec 11–15; Waikaloa, HI.

  • dx.doi.org/10.1124/jpet.112.198895.

  • Received July 31, 2012.
  • Accepted November 28, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleNeuropharmacology

Occupancy of D3 Receptors and ADHD

V. Barth, A. B. Need, E. T. Tzavara, B. Giros, C. Overshiner, S. D. Gleason, M. Wade, A. M. Johansson, K. Perry, G. G. Nomikos and J. M. Witkin
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 501-510; DOI: https://doi.org/10.1124/jpet.112.198895

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Research ArticleNeuropharmacology

Occupancy of D3 Receptors and ADHD

V. Barth, A. B. Need, E. T. Tzavara, B. Giros, C. Overshiner, S. D. Gleason, M. Wade, A. M. Johansson, K. Perry, G. G. Nomikos and J. M. Witkin
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 501-510; DOI: https://doi.org/10.1124/jpet.112.198895
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