Abstract
Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug’s effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25–25 mg/kg every day ip) prior to morphine (10 mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25–25 mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R−/−) mice in the expression phase. In addition, D3R−/− mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (2016YFC0800907), Medical Innovation Program (16CXZ033), National Key Basic Research Program (2015CB553504), Natural Science Foundation of China (No. 81573405) and Beijing Nova Program (xx2014A014).
Author contributions
YL, RRH and MJ conducted the experiments and analyzed the data. RS designed the experiments. YL wrote the draft manuscript. TZ bred the mice. NW initiated this project. RS, JL and GH supervised the experiments and revised the manuscript. We thank Ri-fang Yang (Beijing Institute of Pharmacology and Toxicology) for providing YQA14.
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Lv, Y., Hu, Rr., Jing, M. et al. Selective dopamine D3 receptor antagonist YQA14 inhibits morphine-induced behavioral sensitization in wild type, but not in dopamine D3 receptor knockout mice. Acta Pharmacol Sin 40, 583–588 (2019). https://doi.org/10.1038/s41401-018-0153-0
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DOI: https://doi.org/10.1038/s41401-018-0153-0
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