食欲肽-1受体抑制可阻断乙醇和其他显著强化剂的暴饮暴食式摄入，并导致下丘脑食欲肽免疫反应性降低。
Binge-like consumption of ethanol and other salient reinforcers is blocked by orexin-1 receptor inhibition and leads to a reduction of hypothalamic orexin immunoreactivity.
作者信息
Olney Jeffrey J, Navarro Montserrat, Thiele Todd E
机构信息
Department of Psychology, University of North Carolina, Chapel Hill, North Carolina.
出版信息
Alcohol Clin Exp Res. 2015 Jan;39(1):21-9. doi: 10.1111/acer.12591.
BACKGROUND
Orexin (OX) neurons originating in the lateral hypothalamus (LH) are ideally positioned to modulate reward processing as they form connections with several key brain regions known to be involved in the reward pathway. Consistent with these findings, a growing number of studies have implicated the OX system in modulating the rewarding properties of several drugs of abuse, including ethanol (EtOH). However, the role of the OX system in excessive binge-like EtOH intake remains relatively unexplored. Here, we assessed changes in OX immunoreactivity (IR) in the hypothalamus following repeated cycles of binge-like EtOH drinking and assessed the participation of the OX-1 receptor (OX1R) in binge-like EtOH consumption.
METHODS
The drinking-in-the-dark (DID) paradigm was used to model binge-like EtOH drinking in male C57BL/6J mice. In the first experiment, mice experienced 1 or 3 cycles of binge-like EtOH or sucrose drinking with DID procedures to assess changes in OX IR in distinct subregions of the hypothalamus. Subsequent experiments examined binge-like EtOH and saccharin drinking following peripheral injections of 0.0, 5.0, or 10.0 mg/kg SB-334867 (SB), a selective OX1R antagonist. Finally, mice were given peripheral injections of SB and open-field locomotor activity was measured.
RESULTS
Relative to water drinking controls, binge-like consumption of EtOH and sucrose resulted in a marked reduction in OX IR in the LH. Inhibition of the OX1R via SB blunted EtOH and saccharin drinking, but did not alter open-field locomotor activity.
CONCLUSIONS
Our observed reduction in OX IR in the LH indicates that the OX system in engaged during binge-like consumption of EtOH and sucrose. The observation that inhibition of the OX1R signaling blunted binge-like EtOH, and saccharin drinking suggests that reward-related OX circuits originating in the LH participate in the consumption of salient reinforcers regardless of calories.
背景
起源于下丘脑外侧区（LH）的食欲素（OX）神经元与奖赏通路中几个已知的关键脑区形成连接，因此处于调节奖赏处理的理想位置。与这些发现一致，越来越多的研究表明OX系统参与调节多种滥用药物（包括乙醇（EtOH））的奖赏特性。然而，OX系统在过量类似暴饮暴食的EtOH摄入中的作用仍相对未被探索。在此，我们评估了反复进行类似暴饮暴食的EtOH饮用循环后下丘脑OX免疫反应性（IR）的变化，并评估了OX-1受体（OX1R）在类似暴饮暴食的EtOH消费中的参与情况。
方法
采用黑暗中饮水（DID）范式对雄性C57BL/6J小鼠类似暴饮暴食的EtOH饮用进行建模。在第一个实验中，小鼠通过DID程序经历1或3个类似暴饮暴食的EtOH或蔗糖饮用循环，以评估下丘脑不同亚区中OX IR的变化。随后的实验检查了外周注射0.0、5.0或10.0mg/kg SB-334867（SB，一种选择性OX1R拮抗剂）后类似暴饮暴食的EtOH和糖精饮用情况。最后，给小鼠外周注射SB并测量旷场运动活性。
结果
相对于饮水对照，类似暴饮暴食的EtOH和蔗糖消费导致LH中OX IR显著降低。通过SB抑制OX1R减弱了EtOH和糖精饮用，但未改变旷场运动活性。
结论
我们观察到LH中OX IR降低表明OX系统在类似暴饮暴食的EtOH和蔗糖消费过程中被激活。抑制OX1R信号减弱类似暴饮暴食的EtOH和糖精饮用这一观察结果表明，起源于LH的与奖赏相关的OX回路参与了显著强化物的消费，而与热量无关。
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