Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking.
Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking.
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DOI：
10.1111/j.1460-9568.2009.06844.x
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Aston-Jones G
中科院分区：
文献类型：
--
作者：
Smith RJ;See RE;Aston-Jones G
食欲素/下丘脑泌素系统最近被牵连在奖励加工和成瘾。我们通过在恢复测试之前给予食欲素1受体（OX 1 R）拮抗剂SB-334867或食欲素2受体（OX 2 R）拮抗剂4-吡啶基甲基（S）-叔亮氨酰6，7-二甲氧基-1，2，3，4-四氢异喹啉（4PT）来检查食欲素系统在线索诱导的已熄灭的可卡因寻求恢复中的参与。雄性Sprague-Dawley大鼠在2小时的时间段内自我施用可卡因，持续10天，然后进行消退训练。恢复可卡因寻求引起的介绍音调+光线索先前配对可卡因输注。SB-334867（10、20、30 mg/kg）呈剂量依赖性降低提示诱导的可卡因寻求恢复，而不显著影响晚期消退期间的反应。4PT（10，30 mg/kg）未显著改变线索诱导的恢复。在单独的实验中，SB-334867和4PT的最高剂量对已建立的可卡因自我给药无显著影响，4PT在运动试验中降低自发活动的程度大于SB-334867。最后，SB-334867（30 mg/kg）对操作室中巴甫洛夫可卡因刺激条件反射期间可卡因配对线索的获取没有影响。在巴甫洛夫获取会话之前用SB-334867预处理对随后由这些线索引起的可卡因寻求的线索诱导的恢复没有影响。然而，在第二次恢复期之前用SB-334867预处理显著减弱了线索诱导的恢复的表达。这些结果表明，OX 1 R，而不是OX 2 R的食欲素传输，是必要的恢复可卡因寻求引起的药物配对的线索，并认为食欲素信号是不是关键的可卡因强化或可卡因刺激条件。
The orexin / hypocretin system has recently been implicated in reward-processing and addiction. We examined the involvement of the orexin system in cue-induced reinstatement of extinguished cocaine-seeking by administering the orexin 1 receptor (OX1R) antagonist SB-334867, or the orexin 2 receptor (OX2R) antagonist 4-pyridylmethyl (S)-tert-leucyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4PT), prior to reinstatement testing. Male Sprague-Dawley rats self-administered cocaine in 2-hour sessions for 10 days, followed by extinction training. Reinstatement of cocaine-seeking was elicited by presentation of tone + light cues previously paired with cocaine infusions. SB-334867 (10, 20, 30 mg/kg) dose-dependently decreased cue-induced reinstatement of cocaine-seeking without significantly affecting responding during late extinction. 4PT (10, 30 mg/kg) did not significantly alter cue-induced reinstatement. In separate experiments, the highest doses of SB-334867 and 4PT had no significant effect on established cocaine self-administration, and 4PT reduced spontaneous activity in a locomotor test to a greater extent than SB-334867. Finally, SB-334867 (30 mg/kg) had no effect on the acquisition of cocaine-paired cues during a Pavlovian cocaine-stimulus conditioning session in the operant chamber. Pretreatment with SB-334867 prior to the Pavlovian acquisition session had no effect on subsequent cue-induced reinstatement of cocaine-seeking elicited by those cues. However, pretreatment with SB-334867 prior to a second reinstatement session significantly attenuated the expression of cue-induced reinstatement. These results show that orexin transmission at OX1R, but not OX2R, is necessary for the reinstatement of cocaine-seeking elicited by drug-paired cues, and that orexin signaling is not critical for cocaine reinforcement or cocaine-stimulus conditioning.
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