Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats.
Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats.
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DOI：
10.1016/j.neuropharm.2013.10.010
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发表时间：
2014-02
影响因子：
4.7
通讯作者：
Xi ZX
中科院分区：
文献类型：
--
作者：
Song R;Bi GH;Zhang HY;Yang RF;Gardner EL;Li J;Xi ZX
临床前研究表明，多巴胺 D3 受体 (D3R) 拮抗剂有望用于治疗药物滥用和成瘾。然而，由于半衰期短、毒性或药物治疗功效的临床前研究有限，很少有 D3R 拮抗剂有可能在人体中进行测试。在这里，我们报告了一种新型 D3R 拮抗剂 YQA14，它改善了半衰期和药代动力学特征，并在减弱可卡因奖赏和药物寻求行为复发方面显示出有效的药物治疗功效。实验动物脑电刺激奖励（BSR）是一种高度敏感的实验方法，用于评估药物的奖励效果。我们发现可卡因 (2 mg/kg) 显着增强大鼠的电 BSR（即降低 BSR 的刺激阈值），而单独使用 YQA14 对 BSR 没有影响。 YQA14 预处理可显着且剂量依赖性地减弱可卡因增强的 BSR。 YQA14 还促进了大鼠在早期行为消退过程中对药物寻求行为的消退，并减弱了可卡因或情境线索诱导的药物寻求行为的复发。单独使用 YQA14 不能维持首次实验大鼠或经历过可卡因自我给药的大鼠的自我给药。 YQA14 还抑制重复可卡因诱导的行为敏化的表达。这些发现表明，YQA14 可能具有减弱可卡因服用和可卡因寻求行为的药物治疗潜力。因此，YQA14 作为治疗可卡因成瘾的有前途的药物值得进一步研究。
Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a drug’s rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to drug-seeking behavior. YQA14 alone does not maintain self-administration in either naïve rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-seeking behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction.
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影响因子：
16.2
作者：
Lüscher C;Malenka RC
通讯作者：
Malenka RC
影响因子：
7.3
作者：
Macdonald, GJ;Branch, CL;Ashby, CR
通讯作者：
Ashby, CR
影响因子：
4.7
作者：
Lu, L;Grimm, JW;Shaham, Y
通讯作者：
Shaham, Y
影响因子：
3.3
作者：
DIAZ, J;LEVESQUE, D;SOKOLOFF, P
通讯作者：
SOKOLOFF, P
影响因子：
5.2
作者：
Heidbreder CA;Newman AH
通讯作者：
Newman AH