Florey Neuroscience Institutes, The University of Melbourne, Parkville, Australia.
Br J Pharmacol. 2011 Feb;162(4):880-9. doi: 10.1111/j.1476-5381.2010.01088.x.
The enduring propensity for alcoholics to relapse even following years of abstinence presents a major hurdle for treatment. Here we report a model of relapse following protracted abstinence and investigate the pattern of neuronal activation following cue-induced reinstatement and administration of the orexin₁ receptor antagonist SB-334867 in inbred alcohol-preferring rats.
Rats were trained to self-administer alcohol under operant conditions and divided into two groups: immediate (reinstated immediately following extinction) and delayed (extinguished and then housed for 5 months before reinstatement). Prior to reinstatement, animals were treated with vehicle (immediate n= 11, delayed n= 11) or SB-334867 (20 mg·kg⁻¹ i.p.; immediate n= 6, delayed n= 11). Fos expression was compared between each group and to animals that underwent extinction only.
SB-334867 significantly attenuated cue-induced reinstatement in both groups. Immediate reinstatement increased Fos expression in the nucleus accumbens (NAc), infra-limbic (IL), pre-limbic (PrL), orbitofrontal (OFC) and piriform cortices, the lateral and dorsomedial hypothalamus, central amygdala and basolateral amygdala (BLA), and the bed nucleus of the stria terminalis. Following delayed reinstatement, Fos expression was further elevated in cortical structures. Concurrent with preventing reinstatement, SB-334867 decreased Fos in NAc core, PrL and OFC following immediate reinstatement. Following protracted abstinence, SB-334867 treatment decreased reinstatement-induced Fos in the PrL, OFC and piriform cortices.
Cue-induced alcohol seeking can be triggered following protracted abstinence in rats. The effects of SB-334867 on both behaviour and Fos expression suggest that the orexin system is implicated in cue-induced reinstatement, although some loci may shift following protracted abstinence.
即使在经过多年的戒酒之后，酗酒者仍然存在复饮的倾向，这给治疗带来了重大障碍。在这里，我们报告了一个在长期禁欲后复发的模型，并研究了在同源性酒精偏好大鼠中，线索诱导的复吸和给予食欲素 1 受体拮抗剂 SB-334867 后神经元激活的模式。
大鼠在操作性条件下接受酒精自我给药，并分为两组：即刻（在消退后立即复吸）和延迟（消退后再进行 5 个月的饲养，然后再复吸）。在复吸之前，动物接受载体（即刻 n=11，延迟 n=11）或 SB-334867（20mg·kg⁻¹ i.p.；即刻 n=6，延迟 n=11）处理。将每组与仅接受消退的动物进行比较，观察 Fos 表达。
SB-334867 显著抑制了两组动物的线索诱导复吸。即刻复吸增加了伏隔核（NAc）、下边缘（IL）、前边缘（PrL）、眶额皮质（OFC）和梨状皮质、外侧和背内侧下丘脑、杏仁中央核和基底外侧杏仁核（BLA）以及终纹床核的 Fos 表达。延迟复吸后，皮质结构的 Fos 表达进一步升高。与防止复吸一致，SB-334867 降低了即刻复吸后 NAc 核心、PrL 和 OFC 中的 Fos。在长期禁欲后，SB-334867 处理降低了 PrL、OFC 和梨状皮质中复吸诱导的 Fos。
在大鼠中，经过长期禁欲后，可以引发线索诱导的酒精觅药行为。SB-334867 对行为和 Fos 表达的影响表明，食欲素系统参与了线索诱导的复吸，尽管在长期禁欲后，一些部位可能会发生变化。
