Clemens Kelly J, Castino Matthew R, Cornish Jennifer L, Goodchild Ann K, Holmes Nathan M
1] Department of Psychology, Macquarie University, Sydney, NSW, Australia [2] School of Psychology, University of New South Wales, Sydney, NSW, Australia.
Department of Psychology, Macquarie University, Sydney, NSW, Australia.
Neuropsychopharmacology. 2014 Oct;39(11):2584-93. doi: 10.1038/npp.2014.111. Epub 2014 May 14.
Tobacco addiction involves a transition from occasional, voluntary smoking towards habitual behavior that becomes increasingly resistant to quitting. The development of smoking habits may reflect a loss of behavioral control that can be modeled in rats. This study investigated the behavioral and neural substrates of habit formation in rats exposed to either brief (10 days) or extended (47 days) intravenous (IV) nicotine self-administration training. Following training, the first cohort of rats were exposed to a nicotine devaluation treatment, which involved repeated pairings of IV nicotine with lithium injection. They were then tested for sensitivity of responding to nicotine devaluation under extinction and reinstatement conditions. The second cohort of rats received equivalent self-administration training followed by processing of brain tissue for c-Fos immunohistochemistry. After brief training, devaluation suppressed nicotine-seeking during tests of extinction and reinstatement, confirming that responding is initially sensitive to current nicotine value, and therefore, goal directed. In contrast, after extended training, devaluation had no effect on extinction or reinstatement of responding, indicating that responding had become habitual. Complementary neuroanalysis revealed that extended nicotine self-administration was associated with increased c-Fos expression in brain regions implicated in habitual control of reward seeking, including activation of the dorsolateral striatum and substantia nigra pars compacta. These findings provide evidence of direct devaluation of an IV drug reward, that nicotine self-administration is initially goal-directed but becomes habitual with extended training, and that this behavioral transition involves activation of brain areas associated with the nigrostriatal system.
烟草成瘾涉及从偶尔的、自愿吸烟向习惯性行为的转变，这种习惯性行为对戒烟的抵抗力越来越强。吸烟习惯的形成可能反映了行为控制的丧失，这一点可以在大鼠身上进行模拟。本研究调查了接受短期（10天）或长期（47天）静脉注射尼古丁自我给药训练的大鼠习惯形成的行为和神经基础。训练后，第一组大鼠接受尼古丁贬值处理，即将静脉注射尼古丁与注射锂反复配对。然后在消退和恢复条件下测试它们对尼古丁贬值反应的敏感性。第二组大鼠接受同等的自我给药训练，随后对脑组织进行c-Fos免疫组织化学处理。短期训练后，贬值在消退和恢复测试中抑制了对尼古丁的寻求，证实反应最初对当前尼古丁价值敏感，因此是目标导向的。相比之下，长期训练后，贬值对反应的消退或恢复没有影响，表明反应已变得习惯性。补充性神经分析显示，长期尼古丁自我给药与参与奖励寻求习惯控制的脑区中c-Fos表达增加有关，包括背外侧纹状体和黑质致密部的激活。这些发现提供了静脉注射药物奖励直接贬值的证据，即尼古丁自我给药最初是目标导向的，但随着长期训练会变成习惯性的，并且这种行为转变涉及与黑质纹状体系统相关的脑区激活。
