Short-term adolescent nicotine exposure has immediate and persistent effects on cholinergic systems:: Critical periods, patterns of exposure, dose thresholds
Short-term adolescent nicotine exposure has immediate and persistent effects on cholinergic systems:: Critical periods, patterns of exposure, dose thresholds
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DOI：
10.1038/sj.npp.1300221
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发表时间：
2003-11-01
影响因子：
7.6
通讯作者：
Slotkin, TA
中科院分区：
文献类型：
--
作者：
Abreu-Villaça, Y;Seidler, FJ;Slotkin, TA
在青少年中，尼古丁依赖的症状可以在习惯性吸烟开始之前出现。我们研究了青春期大鼠短期尼古丁暴露的相应胆碱能改变。从出生后第30天开始，大鼠接受为期1周的尼古丁输注或每日两次注射方案，剂量（0.6、2和6 mg/kg/天）设定为达到偶尔至经常吸烟者的血浆水平。在大脑皮层、中脑和海马中，我们评估了烟碱胆碱能受体（nAChR）结合、胆碱乙酰转移酶（ChAT）活性（胆碱能神经末梢的组成性标志物）和[H-3]半胆碱-3（HC-3）与高亲和力胆碱转运蛋白的结合，该转运蛋白对胆碱能突触刺激有反应。在任一给药途径下均观察到nAChR上调，即使在最低剂量下也是如此;在海马中，0.6 mg/kg/天剂量组仅给药2天即可检测到nAChR上调。在中脑中，即使在治疗后1个月，上调仍然显著。青少年尼古丁治疗也产生持久的递减HC-3的结合，可从ChAT的影响，这表明胆碱能突触损伤。同样，这些效应在最低剂量下获得，并在给药后1个月保持显著性。我们的研究结果表明，在青春期，即使是短暂的连续或间歇性尼古丁暴露，也会导致与尼古丁依赖相关的大脑区域胆碱能系统的持久改变。由于在产生的血浆浓度仅为常规吸烟者的十分之一的暴露中检测到这些影响，青少年大脑对尼古丁的极度敏感性可能有助于尼古丁依赖的发生，即使是偶尔吸烟者。
In adolescents, the symptoms of nicotine dependence can appear well before the onset of habitual smoking. We investigated short-term nicotine exposure in adolescent rats for corresponding cholinergic alterations. Beginning on postnatal day 30, rats were given a 1-week regimen of nicotine infusions or twice-daily injections, at doses (0.6, 2, and 6 mg/kg/day) set to achieve plasma levels found in occasional to regular smokers. In the cerebral cortex, midbrain, and hippocampus, we assessed nicotinic cholinergic receptor (nAChR) binding, choline acetyltransferase (ChAT) activity, a constitutive marker for cholinergic nerve terminals, and [H-3] hemicholinium-3 (HC-3) binding to the high-affinity choline transporter, which responds to cholinergic synaptic stimulation. nAChR upregulation was observed with either administration route, even at the lowest dose; in the hippocampus, increases could be detected with as little as 2 days' treatment at 0.6 mg/kg/day. In the midbrain, upregulation was still significant even 1 month post-treatment. Adolescent nicotine treatment also produced lasting decrements in HC-3 binding that were separable from effects on ChAT, suggesting cholinergic synaptic impairment. Again, these effects were obtained at the lowest dose and remained significant 1 month post-treatment. Our results indicate that in adolescence, even a brief period of continuous or intermittent nicotine exposure, elicits lasting alterations in cholinergic systems in brain regions associated with nicotine dependence. As the effects are detected at exposures that produce plasma concentrations as little as one-tenth of those in regular smokers, the exquisite sensitivity of the adolescent brain to nicotine may contribute to the onset of nicotine dependence even in occasional smokers.