Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219.
Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
J Neurosci. 2021 Feb 3;41(5):1046-1058. doi: 10.1523/JNEUROSCI.1830-20.2020. Epub 2020 Dec 2.
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 mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all mutants. Sex differences emerged during the dark (active) phase with 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 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 mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D1+ neurons in the nucleus accumbens (NAc) core and dorsolateral (DLS) striatum in mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in 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 mutation in females. Circadian disruptions are a common symptom of substance use disorders (SUDs) and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent SU. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to SU vulnerability and drug-induced alterations to these genes may augment drug-seeking. 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 in wild-type (WT) and mutant mice at different times of day.
物质使用障碍（SUD）与昼夜节律紊乱有关。昼夜节律转录因子神经元 PAS 结构域蛋白 2（NPAS2）在与奖励相关的大脑区域中丰富，并调节奖励，但在 SUD 中的作用尚不清楚。为了研究 NPAS2 在药物使用中的作用，我们在不同时间点测量了野生型（WT）和 突变小鼠的静脉内可卡因自我给药（获得、剂量反应、递增比例、消退、线索诱导复吸）。在光（不活动）期，所有 突变体的可卡因自我给药、强化、动机和消退反应均增加。在暗（活动）期出现性别差异， 突变仅增加雌性的自我给药、消退反应和复吸，以及雄性和雌性的强化和动机。为了确定循环激素是否导致这些性别差异，我们对 WT 和 突变体雌性进行了卵巢切除术，并证实与假手术对照不同，卵巢切除的突变体小鼠在没有自我给药增加。为了确定纹状体脑区是否在 突变体雌性中被激活，我们测量了可卡因诱导的 ΔFosB 表达。与 WT 相比，在暗期自我给药后， 突变体雌性的伏隔核（NAc）核心和背外侧（DLS）纹状体中的 D1+神经元中，ΔFosB 表达增加。我们还鉴定了可能潜在的靶基因，这些基因可能是 突变体雌性对可卡因的行为反应的基础。这些结果表明，NPAS2 以性别和时间（TOD）特异性的方式调节特定纹状体区域的奖励和活动。循环性激素的增加可能会增强纹状体的激活，从而导致 突变体雌性的影响增加。昼夜节律紊乱是物质使用障碍（SUD）的常见症状，慢性滥用药物会改变昼夜节律，这可能导致随后的 SUD。昼夜节律在行为对药物的反应中很常见，在夜间活动的啮齿动物中，药物敏感性和动机在暗（活动）期达到峰值。新出现的证据将昼夜节律基因与 SUD 易感性联系起来，这些基因对药物的改变可能会增加觅药行为。昼夜节律转录因子神经元 PAS 结构域蛋白 2（NPAS2）在与奖励相关的大脑区域中丰富，并调节奖励，但在 SUD 中的作用尚不清楚。为了研究 NPAS2 在药物使用中的作用，我们在不同时间点测量了野生型（WT）和 突变小鼠的静脉内可卡因自我给药。
