Matzeu Alessandra, Martin-Fardon Rémi
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United States.
Front Neurol. 2018 Aug 28;9:720. doi: 10.3389/fneur.2018.00720. eCollection 2018.
The long-lasting vulnerability to relapse remains the main challenge for the successful treatment of drug addiction. Neural systems that are involved in processing natural rewards and drugs of abuse overlap. However, neuroplasticity that is caused by drug exposure may be responsible for maladaptive, compulsive, and addictive behavior. The orexin (Orx) system participates in regulating numerous physiological processes, including energy metabolism, arousal, and feeding, and is recruited by drugs of abuse. The Orx system is differentially recruited by drugs and natural rewards. Specifically, we found that the Orx system is more engaged by drugs than by non-drugs, such as sweetened condensed milk (SCM) or a glucose saccharin solution (GSS), in an operant model of reward seeking. Although stimuli (S) that are conditioned to cocaine (COC), ethanol, and SCM/GSS equally elicited reinstatement, Orx receptor blockade reversed conditioned reinstatement for drugs vs. non-drugs. Moreover, the hypothalamic recruitment of Orx cells was greater in rats that were tested with the COC S vs. SCM S, indicating of a preferential role for the Orx system in perseverative, compulsive-like COC seeking and not behavior that is motivated by palatable food. Accumulating evidence indicates that the paraventricular nucleus of the thalamus (PVT), which receives major Orx projections, mediates drug-seeking behavior. All Orx neurons contain dynorphin (Dyn), and Orx and Dyn are co-released. In the VTA, they play opposing roles in reward and motivation. To fully understand the physiological and behavioral roles of Orx transmission in the PVT, one important consideration is that Orx neurons that project to the PVT may co-release Orx with another peptide, such as Dyn. The PVT expresses both Orx receptors and κ opioid receptors, suggesting that Orx and Dyn act in tandem when released in the PVT, in addition to the VTA. The present review discusses recent findings that suggest the maladaptive recruitment of Orx/Dyn-PVT neurotransmission by drugs of abuse vs. a highly palatable food reward.
对复吸的长期易感性仍然是成功治疗药物成瘾的主要挑战。参与处理自然奖赏和滥用药物的神经系统存在重叠。然而，药物暴露引起的神经可塑性可能是导致适应不良、强迫性和成瘾行为的原因。食欲素（Orx）系统参与调节多种生理过程，包括能量代谢、觉醒和进食，并被滥用药物所激活。Orx系统被药物和自然奖赏以不同方式激活。具体而言，我们发现在操作性奖赏寻求模型中，与甜炼乳（SCM）或葡萄糖糖精溶液（GSS）等非药物相比，Orx系统对药物的反应更强。尽管与可卡因（COC）、乙醇以及SCM/GSS形成条件反射的刺激（S）均能同等程度地引发复吸，但Orx受体阻断可逆转药物与非药物的条件性复吸。此外，与用SCM刺激测试的大鼠相比，用COC刺激测试的大鼠下丘脑Orx细胞的激活程度更高，这表明Orx系统在持续性、强迫性的COC寻求行为中起优先作用，而不是在由美味食物驱动的行为中起优先作用。越来越多的证据表明，接受主要Orx投射的丘脑室旁核（PVT）介导了觅药行为。所有Orx神经元都含有强啡肽（Dyn），且Orx和Dyn共同释放。在腹侧被盖区（VTA），它们在奖赏和动机方面发挥相反的作用。为了全面了解Orx在PVT中的传递所起的生理和行为作用，一个重要的考虑因素是投射到PVT的Orx神经元可能会与另一种肽（如Dyn）共同释放Orx。PVT同时表达Orx受体和κ阿片受体，这表明除了VTA外，Orx和Dyn在PVT中释放时协同发挥作用。本综述讨论了最近的研究发现，这些发现表明滥用药物与高度美味的食物奖赏对Orx/Dyn-PVT神经传递的适应不良性激活。
