Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Eur J Neurosci. 2015 May;41(9):1149-56. doi: 10.1111/ejn.12866. Epub 2015 Mar 6.
The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1Rs), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light + tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then investigated whether cocaine demand was linked to the cued reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high-demand animals, i.e. animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not that of cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.
食欲素/下丘脑分泌素系统参与多种可卡因成瘾过程，包括与药物相关的环境线索，包括线索诱导的已消除可卡因寻求的复燃和条件性位置偏好的表达。然而，食欲素系统在几种依赖线索较少的行为中不起作用，例如可卡因引发的已消除可卡因寻求的复燃和低努力可卡因自我给药。我们假设可卡因相关的线索，但不是可卡因本身，会激活食欲素-1 受体 (OX1R) 的信号，这种线索激活的 OX1R 信号会增加可卡因的动机。在使用 OX1R 拮抗剂 SB-334867 (SB) 预处理或使用和不使用光+音线索的情况下，通过行为经济学需求曲线分析，在 Sprague-Dawley 大鼠中测量可卡因的动机。当存在可卡因相关线索时，可卡因的需求更高，而 SB 仅在存在这些线索时才降低可卡因的需求。然后，我们研究了可卡因需求是否与可卡因寻求的线索诱导复燃有关，因为这两种程序都部分依赖于以食欲素依赖的方式与可卡因相关的线索。SB 阻断了线索诱导的复燃行为，并且基线需求预测了 SB 的疗效，在高需求动物（即具有最大依赖线索行为的动物）中效果最大。我们得出结论，OX1R 信号增加了可卡因相关线索的强化效力，但不是可卡因本身的强化效力。这支持了我们的观点，即食欲素在条件性线索激活动机反应的能力中起着突出的作用。
