Gilpin Nicholas W, Whitaker Annie M, Baynes Brittni, Abdel Abdelrahim Y, Weil Madelyn T, George Olivier
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Addict Biol. 2014 Jul;19(4):587-92. doi: 10.1111/adb.12021. Epub 2012 Dec 14.
Humans escalate their cigarette smoking over time, and a major obstacle in the field of pre-clinical nicotine addiction research has been the inability to produce escalated nicotine self-administration in rats. In experiment 1, male Wistar rats were trained to respond for nicotine in 2-hour operant sessions, then exposed to chronic intermittent (12 hours/day) nicotine vapor and repeatedly tested for nicotine self-administration at 8-12 hours of withdrawal. Rats were tested intermittently on days 1, 3 and 5 of the vapor exposure procedure, then tested with nicotine vapor exposure on 6-15 consecutive days. Rats exhibited transient increases in operant nicotine responding during intermittent testing, regardless of vapor condition, and this responding returned to baseline levels upon resumption of consecutive-days testing (i.e. nicotine deprivation effect). Nicotine vapor-exposed rats then escalated nicotine self-administration relative to both their own baseline (∼200% increase) and non-dependent controls (∼3× higher). In experiment 2, rats were exposed or not exposed to chronic intermittent nicotine vapor, then tested for spontaneous and precipitated somatic signs of nicotine withdrawal. Eight hours following removal from nicotine vapor, rats exhibited robust mecamylamine-precipitated somatic signs of withdrawal. There was a strong correlation between nicotine flow rate and air-nicotine concentration, and the air-nicotine concentrations used in experiments 1 and 2 resemble concentrations experienced by human smokers. Collectively, these results suggest that chronic intermittent nicotine vapor inhalation produces somatic and motivational signs of nicotine dependence, the latter of which is evidenced by escalation of nicotine self-administration.
随着时间的推移，人类吸烟量会逐渐增加，而临床前尼古丁成瘾研究领域的一个主要障碍是无法在大鼠中诱导出逐渐增加的尼古丁自我给药行为。在实验1中，雄性Wistar大鼠在2小时的操作性实验中接受训练以获取尼古丁，然后暴露于慢性间歇性（每天12小时）尼古丁蒸汽中，并在戒断8 - 12小时后反复测试尼古丁自我给药情况。在蒸汽暴露程序的第1、3和5天对大鼠进行间歇性测试，然后在连续6 - 15天进行尼古丁蒸汽暴露测试。无论蒸汽条件如何，大鼠在间歇性测试期间操作性尼古丁反应均出现短暂增加，而在恢复连续测试时（即尼古丁剥夺效应），这种反应恢复到基线水平。随后，暴露于尼古丁蒸汽的大鼠相对于其自身基线（增加约200%）和非依赖对照组（高出约3倍），尼古丁自我给药量逐渐增加。在实验2中，大鼠暴露或未暴露于慢性间歇性尼古丁蒸汽，然后测试尼古丁戒断的自发和诱发躯体症状。从尼古丁蒸汽中移除8小时后，大鼠表现出强烈的美加明诱发的戒断躯体症状。尼古丁流速与空气 - 尼古丁浓度之间存在很强的相关性，实验1和2中使用的空气 - 尼古丁浓度类似于人类吸烟者所经历的浓度。总体而言，这些结果表明，慢性间歇性吸入尼古丁蒸汽会产生尼古丁依赖的躯体和动机性症状，后者通过尼古丁自我给药量的增加得以证明。
