Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration in Npas2 Mutant Mice
Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration in Npas2 Mutant Mice
复制标题
DOI：
10.1523/jneurosci.1830-20.2020
复制
发表时间：
2021-02-03
影响因子：
5.3
通讯作者：
McClung, Colleen A.
中科院分区：
文献类型：
--
作者：
DePoy, Lauren M.;Becker-Krail, Darius D.;McClung, Colleen A.
物质使用障碍（SUD）与昼夜节律的破坏有关。昼夜节律转录因子神经元PAS结构域蛋白2（NPAS2）在奖赏相关的脑区富集并调节奖赏，但其在SU中的作用尚不清楚。为了研究NPAS2在药物服用中的作用，我们在一天中的不同时间测量了野生型（WT）和NPAS2突变小鼠的静脉内可卡因自我给药（获得、剂量反应、进行性比率、消退、线索诱导的恢复）。在光（非活动）阶段，可卡因自我管理，强化，动机和灭绝的反应增加在所有Npas2突变体。性别差异出现在黑暗（活跃）期与Npas2突变增加自我管理，灭绝的反应，并恢复只有在女性以及男性和女性的强化和动机。为了确定循环激素是否驱动这些性别差异，我们切除了WT和Npas2突变体雌性，并证实与假手术对照不同，切除卵巢的突变体小鼠在自我给药方面没有增加。为了确定Npas2突变女性的纹状体脑区是否被激活，我们测量了可卡因诱导的DFosB表达。相对于WT，在黑暗期自我给药后，Npas2突变雌性大鼠的中脑核（NAc）核心和背外侧（DLS）纹状体中的D1+神经元中DFosB表达增加。我们还确定了潜在的靶基因，可能是Npas2突变女性对可卡因的行为反应的基础。这些结果表明NPAS2以性别和一天中的时间（TOD）特异性方式调节特定纹状体区域的奖励和活动。纹状体激活可以通过循环性激素增强，导致女性Npas2突变的影响增加。
Substance use disorder (SUD) is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and Npas2 mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all Npas2 mutants. Sex differences emerged during the dark (active) phase with Npas2 mutation increasing self-administration, extinction responding, and reinstatement only in females as well as reinforcement and motivation in males and females. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and Npas2 mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in Npas2 mutant females, we measured cocaine-induced DFosB expression. Relative to WT, DFosB expression was increased in D1+ neurons in the nucleus accumbens (NAc) core and dorsolateral (DLS) striatum in Npas2 mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in Npas2 mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day (TOD)-specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of Npas2 mutation in females.