Slotkin Theodore A, Ryde Ian T, Mackillop Emiko A, Bodwell Bethany E, Seidler Frederic J
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Brain Res Bull. 2008 Jul 30;76(5):522-30. doi: 10.1016/j.brainresbull.2008.03.001. Epub 2008 Mar 31.
Neurodevelopmental vulnerability to nicotine extends into adolescence, the stage at which most smokers begin using tobacco. The "sensitization-homeostasis" model postulates that nicotine treatment permanently reprogrammes neural communication, so that underlying functional changes remain present despite the apparent restoration of behavioral normality. We administered nicotine to adolescent rats (postnatal days PN30-47) or adults (postnatal days PN90-107), using regimens that reproduce plasma levels in smokers, and assessed effects on the adenylyl cyclase (AC) signaling cascade, which is involved in nicotine dependence and withdrawal but also mediates numerous other neurotransmitter responses. Evaluations were made in the cerebral cortex, brainstem and cerebellum on PN105, PN110, PN120, PN130 and PN180. Adolescent nicotine exposure elicited persistent suppression of basal AC activity and eventual compromise of responses to beta-adrenergic receptor stimulation, with effects emerging in late adulthood; maximal AC activity as monitored with forskolin was elevated and in general, all the effects were more notable in males. Nicotine treatment in adulthood produced an immediate increase in AC activity in males that disappeared upon withdrawal; there were late-emerging deficits similar to, but smaller in magnitude than those seen with adolescent nicotine exposure. Adolescent treatment greatly exacerbated the response to subsequent nicotine administration in adulthood, producing profound AC deficits during withdrawal that persisted through at least 6 months of age. Our results reinforce the concept that adolescence is a critical developmental period in which nicotine disrupts neural cell signaling in a lasting manner, and provide a mechanistic framework for understanding the biological substrates that determine the relationship between adolescent nicotine exposure and life-long susceptibility to nicotine addiction.
神经发育对尼古丁的易感性会持续到青少年期，而这正是大多数吸烟者开始使用烟草的阶段。“敏化-稳态”模型假定，尼古丁治疗会永久性地重新编程神经通讯，因此尽管行为表面上恢复正常，但潜在的功能变化仍然存在。我们使用能重现吸烟者血浆水平的给药方案，对青春期大鼠（出生后第30 - 47天）或成年大鼠（出生后第90 - 107天）给予尼古丁，并评估其对腺苷酸环化酶（AC）信号级联反应的影响，该信号级联反应与尼古丁依赖和戒断有关，但也介导许多其他神经递质反应。在出生后第105、110、120、130和180天对大脑皮层、脑干和小脑进行评估。青春期接触尼古丁会导致基础AC活性持续受到抑制，并最终损害对β-肾上腺素能受体刺激的反应，这些影响在成年后期才会显现；用福司可林监测到的最大AC活性升高，总体而言，所有这些影响在雄性中更为明显。成年期给予尼古丁会使雄性AC活性立即增加，但戒断后这种增加就会消失；后期出现的缺陷与青春期接触尼古丁时相似，但程度较轻。青春期接受尼古丁治疗会极大地加剧成年期对后续尼古丁给药的反应，在戒断期间会产生严重的AC缺陷，这种缺陷至少持续到6个月大。我们的研究结果强化了这样一个概念，即青春期是一个关键的发育阶段，在此期间尼古丁会以一种持久的方式破坏神经细胞信号传导，并提供了一个机制框架，用于理解决定青春期接触尼古丁与终生尼古丁成瘾易感性之间关系的生物学基础。
