Stowie A C, Amicarelli M J, Prosser R A, Glass J D
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
Neuroscience. 2015 Jan 22;284:171-179. doi: 10.1016/j.neuroscience.2014.08.057. Epub 2014 Oct 6.
The disruptive effects of cocaine on physiological, behavioral and genetic processes are well established. However, few studies have focused on the actions of cocaine on the adult circadian timekeeping system, and none have explored the circadian implications of long-term (weeks to months) cocaine exposure. The present study was undertaken to explore the actions of such long-term cocaine administration on core circadian parameters in mice, including rhythm period, length of the nocturnal activity period and photic entrainment. For cocaine dosing over extended periods, cocaine was provided in drinking water using continuous and scheduled regimens. The impact of chronic cocaine on circadian regulation was evidenced by disruptions of the period of circadian entrainment and intrinsic free-running circadian period. Specifically, mice under a skeleton photoperiod (1-min pulse of dim light delivered daily) receiving continuous ad libitum cocaine entrained rapidly to the light pulse at activity onset. Conversely, water controls entrained more slowly at activity offset through a process of phase-delays, which resulted in their activity rhythms being entrained 147° out of phase with the cocaine group. This pattern persisted after cocaine withdrawal. Next, mice exposed to scheduled daily cocaine presentations exhibited free-running periods under constant darkness that were significantly longer than water controls and which also persisted after cocaine withdrawal. These cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence.
可卡因对生理、行为和遗传过程的破坏作用已得到充分证实。然而，很少有研究关注可卡因对成年生物钟系统的作用，且尚无研究探讨长期（数周数月）接触可卡因对昼夜节律的影响。本研究旨在探究长期给予可卡因对小鼠核心昼夜节律参数的作用，包括节律周期、夜间活动期时长和光诱导同步。为了长期给予可卡因，采用持续给药和定时给药方案，将可卡因添加到饮用水中。慢性可卡因对昼夜节律调节的影响表现为昼夜节律同步周期和内在自由运转昼夜周期的紊乱。具体而言，在骨架光周期（每天给予1分钟暗光脉冲）条件下，自由摄取持续添加可卡因的小鼠在活动开始时迅速与光脉冲同步。相反，饮水对照组通过相位延迟过程在活动结束时同步较慢，这导致它们的活动节律与可卡因组相差147°。这种模式在撤药后仍然存在。接下来，每天定时给予可卡因的小鼠在持续黑暗条件下的自由运转周期明显长于饮水对照组，且在撤药后也依然如此。这些由可卡因引起的生物钟定时紊乱可能会产生慢性心理和生理应激，从而导致可卡因使用和依赖增加。
