A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps.
A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps.
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DOI：
10.1016/j.pbb.2015.12.010
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Stein EA
中科院分区：
文献类型：
--
作者：
Brynildsen JK;Najar J;Hsu LM;Vaupel DB;Lu H;Ross TJ;Yang Y;Stein EA
Although osmotic minipumps are a reliable method for inducing nicotine dependence in rodents, continuous nicotine administration does not accurately model the intermittent pattern of nicotine intake in cigarette smokers. Our objectives, therefore, were to investigate whether intermittent nicotine delivery via osmotic minipumps could induce dependence in rats, and to compare the magnitude and duration of withdrawal following forced abstinence from intermittent nicotine to that induced by continuous nicotine administration. In order to administer nicotine intermittently, rats were surgically implanted with saline-filled osmotic minipumps attached to polyethylene tubing that contained hourly unit doses of nicotine alternating with mineral oil to mimic “injections”. Three doses of nicotine (1.2, 2.4, and 4.8 mg/kg/day) and saline were administered for 14 days using this method. In order to compare our intermittent delivery method with the more traditional continuous nicotine delivery, a second group of rats were implanted with minipumps attached to tubing that delivered continuous nicotine for 14 days. Rats were administered a 1.5 mg/kg subcutaneous (SC) mecamylamine challenge and observed for somatic signs of withdrawal on days 7, 14, 21, and 28 following minipump implantation. Fifteen somatic withdrawal signs were summed within a 50-minute observation period to obtain a composite Dependence Score. A generalized linear mixed-effects model revealed a significant Day × Dose × Method interaction. Amongst continuously-treated rats, only 4.8 mg/kg/d nicotine resulted in dependence scores significantly greater than those of controls at 14 days of exposure. In contrast, all intermittent nicotine groups showed significantly higher scores beginning at 7 days of exposure and persisting beyond 7 days of abstinence. In general, intermittent delivery produced a more robust withdrawal syndrome than continuous delivery, and did so at a lower dose threshold and with greater persistence after forced abstinence.
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