Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 416B, Charleston, SC 29425, USA.
Neuropharmacology. 2012 Dec;63(7):1201-7. doi: 10.1016/j.neuropharm.2012.07.044. Epub 2012 Aug 7.
The orexin/hypocretin system has been implicated in multiple phases of drug addiction. Acute orexin receptor blockade with the orexin-1 receptor (OX1R) antagonist, SB-334867, has been found to reduce cocaine seeking after cocaine self-administration. As repeated drug dosing can have differential effects and is more clinically relevant than acute dosing, in the current study we examined the effects of repeated SB-334867 on cocaine self-administration, extinction, and reinstatement to cocaine seeking in Sprague-Dawley rats. We found that repeated SB-334867 (10 mg/kg/day) had no effect on established cocaine self-administration. Repeated SB-334867 (both 10 and 20 mg/kg) attenuated cocaine seeking during extinction; however, this effect was only observed when animals had no prior experience with SB-334867 and when SB-334867 was administered prior to, but not after, daily extinction sessions. Notably, daily treatment with SB-334867 (10 mg/kg) during extinction increased subsequent cue-induced reinstatement, whereas repeated SB-334867 (20 mg/kg) administration during extinction enabled acute SB-334867 to reduce cue-induced reinstatement. Repeated SB-334867 treatment (10 or 20 mg/kg) failed to affect reinstatement induced by priming injections of cocaine (10 mg/kg). These results show that repeated inhibition of OX1R-mediated signaling exerts a lasting and specific role in mediating environmentally activated cocaine seeking.
食欲素/下丘脑分泌素系统参与了药物成瘾的多个阶段。研究发现，使用食欲素-1 受体（OX1R）拮抗剂 SB-334867 急性阻断食欲素受体，可减少可卡因自我给药后的可卡因觅药行为。由于重复给药可能会产生不同的效果，且比急性给药更具临床相关性，因此在本研究中，我们在 Sprague-Dawley 大鼠中研究了重复给予 SB-334867 对可卡因自我给药、消退和可卡因觅药复燃的影响。我们发现，重复给予 SB-334867（10mg/kg/天）对已建立的可卡因自我给药没有影响。重复给予 SB-334867（10 和 20mg/kg）均可减弱消退期间的可卡因觅药行为；然而，这种效应仅在动物没有 SB-334867 先前经验且 SB-334867 在每日消退前而非消退后给药时才观察到。值得注意的是，在消退期间每日给予 SB-334867（10mg/kg）会增加随后线索诱导的复燃，而在消退期间给予重复 SB-334867（20mg/kg）则使急性 SB-334867 能够减少线索诱导的复燃。重复给予 SB-334867（10 或 20mg/kg）治疗未能影响可卡因（10mg/kg）引发的复燃。这些结果表明，重复抑制 OX1R 介导的信号转导在介导环境激活的可卡因觅药方面发挥持久而特定的作用。
