Franke Ryan M, Park Minjung, Belluzzi James D, Leslie Frances M
Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA.
Eur J Neurosci. 2008 Jun;27(11):2952-61. doi: 10.1111/j.1460-9568.2008.06253.x.
Clinical studies have demonstrated an increased incidence of substance misuse and obesity in adolescents whose mothers smoked during pregnancy. Although dopamine systems that mediate natural and drug-induced reinforcement have been shown in animal studies to be altered by gestational nicotine treatment, it is not clear whether there are concomitant changes in reinforcement sensitivity. To test whether prenatal nicotine exposure influences sensitivity to natural and drug rewards, timed pregnant rats were implanted with osmotic minipumps delivering saline or nicotine (3 mg/kg/day) from gestational day 4 to 18. Male offspring were tested as adolescents, on postnatal day 32, for operant responding maintained by sucrose pellets or i.v. cocaine (200 or 500 mug/kg per injection). Cocaine-induced stereotypy and c-fos mRNA expression in cortex and striatum were also examined. Complex changes in reward circuitry were observed in the offspring of nicotine-exposed dams. Nicotine-exposed adolescents did not self-administer the low dose of cocaine, but, at the higher dose, exhibited significantly greater cocaine intake and c-fos mRNA expression in nucleus accumbens than did controls. In contrast, control animals showed significantly greater drug-induced stereotypy at both cocaine doses. Operant responding maintained by sucrose was also influenced by gestational nicotine exposure. At a fixed ratio (FR) 1 schedule, although the number of pellets eaten by the two experimental groups was equivalent, more pellets were left uneaten by nicotine-exposed offspring. At FR2 and FR5 schedules, the responding maintained by sucrose pellets was lower in nicotine-exposed offspring. These findings suggest that nicotine exposure during gestation may induce changes in both natural and drug reward pathways.
临床研究表明，母亲在孕期吸烟的青少年中，物质滥用和肥胖的发生率有所增加。尽管在动物研究中已表明，介导自然强化和药物诱导强化的多巴胺系统会因孕期尼古丁处理而改变，但尚不清楚强化敏感性是否会同时发生变化。为了测试产前尼古丁暴露是否会影响对自然奖励和药物奖励的敏感性，在妊娠第4天至18天，给定时怀孕的大鼠植入渗透微型泵，分别输注生理盐水或尼古丁（3毫克/千克/天）。雄性后代在出生后第32天作为青少年进行测试，以检测由蔗糖颗粒或静脉注射可卡因（每次注射200或500微克/千克）维持的操作性反应。还检查了可卡因诱导的刻板行为以及皮质和纹状体中c-fos mRNA的表达。在尼古丁暴露母鼠的后代中观察到奖励回路的复杂变化。暴露于尼古丁的青少年不会自我给药低剂量的可卡因，但在高剂量时，与对照组相比，伏隔核中的可卡因摄入量和c-fos mRNA表达显著更高。相比之下，在两种可卡因剂量下，对照动物的药物诱导刻板行为都显著更强。由蔗糖维持的操作性反应也受到孕期尼古丁暴露的影响。在固定比率（FR）1的时间表下，尽管两个实验组吃掉的颗粒数量相当，但暴露于尼古丁的后代未吃掉的颗粒更多。在FR2和FR5的时间表下，暴露于尼古丁的后代中由蔗糖颗粒维持的反应较低。这些发现表明，孕期尼古丁暴露可能会导致自然奖励和药物奖励途径都发生变化。
