Selective dopamine D3 receptor antagonist YQA14 inhibits morphine-induced behavioral sensitization in wild type, but not in dopamine D3 receptor knockout mice

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.

Keywords: YQA14; behavioral sensitization; dopamine D3 receptor; dopamine D3 receptor knockout mice; morphine.

Fig. 1

Effects of the chronic administration of YQA14 on the acquisition of morphine-induced behavioral sensitization in mice. a Experimental protocol for saline, morphine, and YQA14 injections. b Time courses of morphine-induced hyperactivity and behavioral sensitization with or without YQA14 pretreatment. Mean ± SEM. *P < 0.05 on Day 5 vs. Day 4; and ***P < 0.001 on Day 6, 7, 8, 9, and 10 vs. Day 4. ^#P < 0.05; ^##P < 0.01; and ^###P < 0.001 vs. the morphine + vehicle group. c Morphine priming produced a significant increase in locomotor activity 7 days after the last morphine injection. ***P < 0.001 vs. the saline group. This effect was attenuated in the groups that received chronic treatment with YQA14. ^#P < 0.05 vs. morphine treatment alone. Mean ± SEM

Fig. 2

Effects of the acute administration of YQA14 on the expression of morphine-induced locomotor sensitization in mice. a Experimental protocol for saline, morphine and YQA14 injections. b Time courses of morphine-induced hyperactivity and behavioral sensitization. Mean ± SEM. c Morphine priming produced a significant increase in locomotor activity 7 days after the last morphine injection. ***P < 0.001 vs. the saline group. This effect was attenuated in the groups that received acute pretreatment with YQA14. ^#P < 0.05 vs. the morphine treatment group. Mean ± SEM

Fig. 3

Effects of the acute administration of YQA14 on the expression of morphine-induced locomotor sensitization in WT and D3R^−/− mice. a Experimental protocol for morphine and YQA14 injections. b YQA14 administration attenuated the expression of morphine-induced locomotor sensitization in WT mice, but not in D3R^−/− mice. ^###P < 0.001 vs. morphine treatment in WT mice. *P < 0.05 compared to the WT morphine group. Mean ± SEM