Department of 1OB/GYN and Reproductive Science, Yale University School of Medicine, New Haven, CT 06520, USA.
J Physiol. 2013 Apr 1;591(7):1951-66. doi: 10.1113/jphysiol.2012.246983. Epub 2013 Jan 14.
Hypocretin (orexin), a neuropeptide synthesized exclusively in the perifornical/lateral hypothalamus, is critical for drug seeking and relapse, but it is not clear how the circuitry centred on hypocretin-producing neurons (hypocretin neurons) is modified by drugs of abuse and how changes in this circuit might alter behaviours related to drug addiction. In this study, we show that repeated, but not single, in vivo cocaine administration leads to a long-lasting, experience-dependent potentiation of glutamatergic synapses on hypocretin neurons in mice following a cocaine-conditioned place preference (CPP) protocol. The synaptic potentiation occurs postsynaptically and probably involves up-regulation of AMPA-type glutamate receptors on hypocretin neurons. Phosphorylation of cAMP response element-binding protein (CREB) is also significantly increased in hypocretin neurons in cocaine-treated animals, suggesting that CREB-mediated pathways may contribute to synaptic potentiation in these cells. Furthermore, the potentiation of synaptic efficacy in hypocretin neurons persists during cocaine withdrawal, but reverses to baseline levels after prolonged abstinence. Finally, the induction of long-term potentiation (LTP) triggered by a high-frequency stimulation is facilitated in hypocretin neurons in cocaine-treated mice, suggesting that long-lasting changes in synapses onto hypocretin neurons would probably be further potentiated by other stimuli (such as concurrent environmental cues) paired with the drug. In summary, we show here that hypocretin neurons undergo experience-dependent synaptic potentiation that is distinct from that reported in other reward systems, such as the ventral tegmental area, following exposure to cocaine. These findings support the idea that the hypocretin system is important for behavioural changes associated with cocaine administration in animals and humans.
下丘脑外侧区/穹窿周区产生的神经肽食欲素（orexin）对于觅药和复吸至关重要，但目前尚不清楚以食欲素神经元为中心的环路是如何被滥用药物改变的，以及该环路的变化如何改变与药物成瘾相关的行为。在这项研究中，我们发现，重复但不是单次给予可卡因，会导致在可卡因条件性位置偏爱（CPP）方案后，在小鼠中产生持久的、依赖经验的食欲素神经元上谷氨酸能突触传递增强。这种突触增强发生在突触后，并可能涉及食欲素神经元上 AMPA 型谷氨酸受体的上调。可卡因处理动物的食欲素神经元中 cAMP 反应元件结合蛋白（CREB）的磷酸化也显著增加，这表明 CREB 介导的途径可能有助于这些细胞中的突触增强。此外，在可卡因戒断期间，突触效能的增强持续存在，但在长时间禁欲后恢复到基线水平。最后，在可卡因处理的小鼠中，高频刺激引发的长时程增强（LTP）更容易诱导，这表明与药物同时出现的其他刺激（如环境线索）可能进一步增强食欲素神经元上突触的长期变化。总之，我们在这里表明，食欲素神经元经历了依赖于经验的突触增强，这与暴露于可卡因后其他奖励系统（如腹侧被盖区）中报道的情况不同。这些发现支持这样一种观点，即食欲素系统对于动物和人类中与可卡因给药相关的行为变化很重要。
