Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, South Australia, Australia.
Discipline of Physiology, Adelaide Medical School, University of Adelaide, South Australia, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia, Australia.
Brain Behav Immun. 2018 Jan;67:181-193. doi: 10.1016/j.bbi.2017.08.021. Epub 2017 Aug 30.
Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.
昼夜节律会影响药物引起的奖赏行为和先天免疫系统。与奖赏相关的行为和免疫反应的高峰通常发生在啮齿动物的活动（黑暗）期。虽然免疫系统，特别是 Toll 样受体 4（TLR4，一种先天免疫受体）在药物引起的奖赏中的作用正越来越受到关注，但尚不清楚其作用是否会根据光照周期而变化。因此，本研究旨在描述光照周期的阶段和先天免疫系统的状态对酒精奖赏行为的影响，随后确定针对药物奖赏的免疫成分的疗效是否取决于光照周期。本研究表明，在黑暗周期中，小鼠表现出更大的酒精诱导的条件性位置偏好和酒精双瓶选择偏好。这种效应与奖赏、口渴和免疫相关基因的升高重叠。TLR4 拮抗剂(+)-纳曲酮的给药减少了与免疫相关的基因 mRNA 表达和酒精偏好，其作用在黑暗周期最为明显。然而，(+)-纳曲酮，与其他 TLR4 拮抗剂一样，表现出脱靶的副作用，整体蔗糖摄入量显著减少——这一效应可能归因于酪氨酸羟化酶（Th）mRNA 表达水平的降低。总之，该研究强调了 TLR4 在小鼠的自然和酒精奖赏样行为中存在与时间相关的影响。
