Kant G J, Bauman R A, Feaster S R, Anderson S M, Saviolakis G A, Garcia G E
Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
Pharmacol Biochem Behav. 2001 Oct-Nov;70(2-3):209-18. doi: 10.1016/s0091-3057(01)00596-2.
Thousands of soldiers who served in the Gulf War have symptoms that have been collectively termed Gulf War Illness (GWI). It has been suggested that a combination of operational stress and pyridostigmine, a drug given as a pretreatment to protect soldiers against the effects of exposure to nerve agents, might have had unexpected adverse health effects causing these symptoms. Our laboratory has previously modeled operational stress in rats using a paradigm of around-the-clock intermittent signalled footshock. In the present studies, this model was used to investigate the potential synergistic effects of chronic stress and pyridostigmine on physiology and behavior. Seventy-two rats were trained to perform an alternation lever pressing task to earn their entire daily food intake. The rats were then implanted with osmotic minipumps containing vehicle, pyridostigmine (25 mg/ml pyridostigmine bromide) or physostigmine (20 mg/ml eserine hemisulfate). The pumps delivered 1 microl/h, which resulted in a cumulative dosing of approximately 1.5 mg/kg/day of pyridostigmine or 1.2 mg/kg/day of physostigmine, equimolar doses of the two drugs. The rats were then returned to their home cages where performance continued to be measured 24 h/day. After 4 days, 24 of the 72 rats were trained to escape signalled footshock (avoidance-escape group) and 24 other rats (yoked-stressed group) were each paired to a rat in the avoidance-escape group. The remaining 24 rats were not subjected to footshock (unstressed group). Shock trials were intermittently presented in the home cage 24 h/day for 3 days, while alternation performance continued to be measured. Since only 12 test cages were available, each condition was repeated to achieve a final n of six rats per group. Pyridostigmine and physostigmine each decreased blood acetylcholinesterase levels by approximately 50%. Physostigmine also decreased brain cortical acetylcholinesterase levels by approximately 50%, while pyridostigmine had no effect on cortical acetylcholinesterase activity. Alternation performance was impaired on the first day of stress and then recovered. Neither pyridostigmine nor physostigmine affected performance in the absence of stress or increased the effects of stress alone. Corticosterone was significantly increased in the yoked stress group compared to unstressed controls. These data suggest that pyridostigmine does not exacerbate the effects of stress on performance or levels of stress hormones. Furthermore, these data do not suggest that stress enables pyridostigmine to cross the blood brain barrier.
数千名曾在海湾战争中服役的士兵出现了一些症状，这些症状被统称为海湾战争综合征（GWI）。有人认为，作战压力与吡啶斯的明（一种作为预处理药物给予士兵以保护其免受接触神经毒剂影响的药物）的联合作用，可能产生了意想不到的不良健康影响，从而导致了这些症状。我们实验室之前使用昼夜间歇性信号足部电击范式在大鼠中模拟作战压力。在本研究中，该模型被用于研究慢性应激和吡啶斯的明对生理和行为的潜在协同作用。72只大鼠接受训练，通过交替按压杠杆任务来获取其全天的食物摄入量。然后给大鼠植入含有赋形剂、吡啶斯的明（25毫克/毫升溴化吡啶斯的明）或毒扁豆碱（20毫克/毫升半硫酸依色林）的渗透微型泵。这些泵以每小时1微升的速度给药，这导致吡啶斯的明的累积给药量约为1.5毫克/千克/天，毒扁豆碱的累积给药量约为1.2毫克/千克/天，这两种药物为等摩尔剂量。然后将大鼠放回它们的饲养笼中，在那里每天24小时持续测量其行为表现。4天后，72只大鼠中的24只接受训练以逃避信号足部电击（逃避 - 躲避组），另外24只大鼠（配对应激组）分别与逃避 - 躲避组中的一只大鼠配对。其余24只大鼠不接受足部电击（无应激组）。电击试验在饲养笼中每天24小时间歇性进行3天，同时继续测量交替行为表现。由于只有12个测试笼可用，每个条件重复进行，以使每组最终有6只大鼠。吡啶斯的明和毒扁豆碱各自使血液中的乙酰胆碱酯酶水平降低了约50%。毒扁豆碱还使大脑皮层的乙酰胆碱酯酶水平降低了约50%，而吡啶斯的明对皮层乙酰胆碱酯酶活性没有影响。在应激的第一天，交替行为表现受损，然后恢复。在无应激情况下，吡啶斯的明和毒扁豆碱均不影响行为表现，也不会单独增加应激的影响。与无应激对照组相比，配对应激组中的皮质酮水平显著升高。这些数据表明，吡啶斯的明不会加剧应激对行为表现或应激激素水平的影响。此外，这些数据并不表明应激能使吡啶斯的明穿过血脑屏障。
