Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA.
Addict Biol. 2018 Jan;23(1):6-15. doi: 10.1111/adb.12441. Epub 2016 Aug 24.
Hypothalamic orexin/hypocretin (Orx/Hcrt) neurons are thought to mediate both food-reinforced behaviors and behavior motivated by drugs of abuse. However, the relative role of the Orx/Hcrt system in behavior motivated by food versus drugs of abuse remains unclear. This investigation addressed this question by contrasting hypothalamic Orx/Hcrt neuronal activation associated with reinstatement of reward seeking induced by stimuli conditioned to cocaine (COC) versus highly palatable food reward, sweetened condensed milk (SCM). Orx/Hcrt neuronal activation in the lateral hypothalamus, dorsomedial hypothalamus and perifornical area, determined by dual c-fos/orx immunocytochemistry, was quantified in rat brains, following reinstatement of reward seeking induced by a discriminative stimulus (S ) conditioned to COC or SCM. The COC S and SCM S initially produced the same magnitude of reward seeking. However, over four subsequent tests, behavior induced by the SCM S decreased to extinction levels, whereas reinstatement induced by the COC S perseverated at undiminished levels. Following both the first and fourth tests, the percentage of Orx/Hcrt cells expressing Fos was significantly increased in all hypothalamic subregions in rats tested with the COC S but not rats tested with the SCM S . These findings point toward a role for the Orx/Hcrt system in perseverating, compulsive-like COC seeking but not behavior motivated by palatable food. Moreover, analysis of the Orx/Hcrt recruitment patterns suggests that failure of Orx/Hcrt neurons in the lateral hypothalamus to respond to inhibitory inputs from Orx/Hcrt neurons in the dorsomedial hypothalamus/perifornical area may contribute to the perseverating nature of COC seeking.
下丘脑食欲素/下丘脑泌素（Orx/Hcrt）神经元被认为介导了食物强化行为和药物滥用行为。然而，Orx/Hcrt 系统在食物动机和药物滥用动机行为中的相对作用仍不清楚。本研究通过对比可卡因（COC）条件刺激与高可口食物奖励——甜炼乳（SCM）诱导的奖赏寻求复燃时下丘脑 Orx/Hcrt 神经元的激活情况来解决这个问题。通过双重 c-fos/orx 免疫细胞化学，在大鼠大脑中定量测定了外侧下丘脑、下丘脑背内侧核和穹窿周区的 Orx/Hcrt 神经元激活情况，这些区域是由 COC 或 SCM 条件刺激诱导的奖赏寻求复燃所决定的。最初，COC S 和 SCM S 诱导的奖赏寻求具有相同的强度。然而，在随后的四次测试中，SCM S 诱导的行为减少到消退水平，而 COC S 诱导的复燃则保持在未减弱的水平。在第一次和第四次测试后，用 COC S 测试的大鼠所有下丘脑亚区中表达 Fos 的 Orx/Hcrt 细胞的百分比显著增加，而用 SCM S 测试的大鼠则没有增加。这些发现表明，Orx/Hcrt 系统在持续、强迫性的 COC 寻求中起作用，但在美味食物动机行为中不起作用。此外，对 Orx/Hcrt 募集模式的分析表明，外侧下丘脑的 Orx/Hcrt 神经元对来自下丘脑背内侧核/穹窿周区的 Orx/Hcrt 神经元的抑制性输入反应失败，可能导致 COC 寻求的持续性质。
