Nicotine effects in adolescence and adulthood on cognition and α₄β₂-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia.
Nicotine effects in adolescence and adulthood on cognition and α₄β₂-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia.
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DOI：
10.1007/s00213-014-3800-2
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发表时间：
2015-05
影响因子：
3.4
通讯作者：
Chambers, R. Andrew
中科院分区：
文献类型：
--
作者：
Berg, Sarah A.;Sentir, Alena M.;Bell, Richard L.;Engleman, Eric A.;Chambers, R. Andrew
关键词：
精神分裂症中尼古丁的使用传统上被解释为认知和/或烟碱乙酰胆碱能受体（nAChR）异常的“自我药物治疗”。我们在精神分裂症的神经发育大鼠模型中测试了这一假设，该模型显示出增加的成瘾行为，包括增强的尼古丁强化和药物寻求。在新生儿腹侧海马损伤（NVHL）和SHAM手术大鼠中检查尼古丁透皮贴剂（5 mg/kg/天vs安慰剂× 10天，青春期或成年期）对随后的径向臂迷宫学习（15次）和额叶-皮质-纹状体nAChR密度（α4β2; [3 H]-地棘蛙素结合）的影响。与SHAM相比，尼古丁史对NVHL认知缺陷的影响没有差异。尼古丁史产生最小的认知影响，同时增加迷宫中的食物奖励消费，与NVHL诱导的过度消费相结合。在最后一次迷宫训练前给予急性尼古丁（0.5 mg/kg），仅对有尼古丁贴片史的大鼠的迷宫表现产生适度改善，但对NVHL无差异。与精神分裂症吸烟者与非吸烟者和健康对照者中β2 nAChR结合的体内神经成像一致，成人NVHL显示MPFC中nAChR结合减少12%（p<0.05），但腹侧纹状体中没有（<5%变化，p> 0.40），而尼古丁历史升高了两个区域的nAChR（> 30%，p<0.001），而不与NVHL相互作用。青少年与成人尼古丁暴露没有改变nAChRs差异。尽管在吸烟者中复制尼古丁诱导的nAChR上调，并在精神分裂症相关的nAChR密度模式方面证明了NVHL的有效性，但这些研究结果并不支持解释精神分裂症中尼古丁使用增加的假设，即尼古丁在治疗上改变认知或nAChR密度的疾病特异性作用。
Nicotine use in schizophrenia has traditionally been explained as ‘self-medication’ of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food–reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p<0.05) but not ventral striatum (<5% changes, p>.40), whereas nicotine history elevated nAChRs across both regions (>30%, p<0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. Although replicating nicotine-induced up-regulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities.
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