Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, New Jersey, USA.
Florey Institute for Neuroscience and Mental Health, Parkville, Australia.
Addict Biol. 2020 Jul;25(4):e12795. doi: 10.1111/adb.12795. Epub 2019 Jul 11.
Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as after a 2-week period of abstinence, to relate the number of LH orexin cells to economic demand for cocaine. We also knocked down LH orexin expression with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. We found that animals with greater baseline motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a 2-week abstinence from cocaine, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence, indicating that orexin expression is a persistent marker for demand. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual motivation for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.
外侧下丘脑 (LH) 食欲素神经元信号与寻求和使用滥用药物的动机有关。暴露于滥用药物会导致 LH 食欲素神经元数量增加。我们试图确定 LH 食欲素神经元的数量是否与我们的行为经济学 (BE) 范式中可卡因的动机（需求）个体差异有关，以及这些细胞的敲低是否预测经济需求的变化。我们在 BE 范式后立即以及 2 周的戒断期后定量测定 LH 食欲素细胞数量，以将 LH 食欲素细胞数量与可卡因的经济需求联系起来。我们还使用食欲素的反义 MORPHOLINO 敲低 LH 食欲素表达，以确定减少食欲素数量如何影响可卡因需求。我们发现，可卡因基线动机更大（需求弹性更低）的动物具有更多的 LH 食欲素神经元。在可卡因戒断 2 周后，LH 食欲素神经元的数量预测了戒断前可卡因的经济需求，表明食欲素表达是需求的持久标志物。使用反义 MORPHOLINO 减少 LH 食欲素细胞数量会降低可卡因的动机（增加需求弹性），而不会影响基线消费。此外，反义治疗后剩余 LH 食欲素神经元的数量与可卡因的个体动机相关。这些研究表明，内源性 LH 食欲素神经元的数量在可卡因动机的个体差异中起作用。
