Department of Psychiatry, Ribicoff Research Facilities, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Biol Psychiatry. 2010 Apr 15;67(8):753-60. doi: 10.1016/j.biopsych.2009.12.035. Epub 2010 Feb 26.
Orexin (hypocretin) signaling is implicated in drug addiction and reward, but its role in feeding and food-motivated behavior remains unclear.
We investigated orexin's contribution to food-reinforced instrumental responding using an orexin 1 receptor (Ox1r) antagonist, orexin -/- (OKO) and littermate wildtype (WT) mice, and RNAi-mediated knockdown of orexin. C57BL/6J (n = 76) and OKO (n = 39) mice were trained to nose poke for food under a variable ratio schedule of reinforcement. After responding stabilized, a progressive ratio schedule was initiated to evaluate motivation to obtain food reinforcement.
Blockade of Ox1r in C57BL/6J mice impaired performance under both the variable ratio and progressive ratio schedules of reinforcement, indicating impaired motivational processes. In contrast, OKO mice initially demonstrated a delay in acquisition but eventually achieved levels of responding similar to those observed in WT animals. Moreover, OKO mice did not differ from WT mice under a progressive ratio schedule, indicating delayed learning processes but no motivational impairments. Considering the differences between pharmacologic blockade of Ox1r and the OKO mice, animals with RNAi mediated knockdown of orexin were then generated and analyzed to eliminate possible developmental effects of missing orexin. Orexin gene knockdown in the lateral hypothalamus in C57BL/6J mice resulted in blunted performance under both the variable ratio and progressive ratio schedules, resembling data obtained following Ox1r antagonism.
The behavior seen in OKO mice likely reflects developmental compensation often seen in mutant animals. These data suggest that activation of the Ox1r is a necessary component of food-reinforced responding, motivation, or both in normal mice.
食欲素（Hypocretin）信号与药物成瘾和奖赏有关，但它在摄食和食物动机行为中的作用尚不清楚。
我们使用食欲素 1 型受体（Ox1r）拮抗剂、食欲素敲除（OKO）和同窝野生型（WT）小鼠以及食欲素的 RNAi 介导敲低，研究了食欲素在食物强化仪器反应中的作用。C57BL/6J（n = 76）和 OKO（n = 39）小鼠接受训练，通过可变比率强化程序进行鼻探测以获取食物。在反应稳定后，启动了一个递增比率程序，以评估获得食物强化的动机。
在 C57BL/6J 小鼠中，Ox1r 的阻断会损害强化程序下的可变比率和递增比率表现，表明动机过程受损。相比之下，OKO 小鼠最初表现出获得的延迟，但最终达到与 WT 动物相似的反应水平。此外，在递增比率程序下，OKO 小鼠与 WT 小鼠没有差异，表明学习过程延迟但没有动机损伤。考虑到 Ox1r 阻断的药理学与 OKO 小鼠之间的差异，随后生成并分析了具有 RNAi 介导的食欲素敲低的动物，以消除缺失食欲素可能产生的发育影响。在 C57BL/6J 小鼠的外侧下丘脑进行食欲素基因敲低，导致在可变比率和递增比率程序下的表现减弱，类似于 Ox1r 拮抗后获得的数据。
OKO 小鼠的行为可能反映了突变动物中常见的发育代偿。这些数据表明，在正常小鼠中，Ox1r 的激活是食物强化反应、动机或两者的必要组成部分。
