Cohen Ami, Treweek Jennifer, Edwards Scott, Leão Rodrigo Molini, Schulteis Gery, Koob George F, George Olivier
The Scripps Research Institute, La Jolla, CA, USA.
Addict Biol. 2015 Jan;20(1):56-68. doi: 10.1111/adb.12077. Epub 2013 Jul 22.
Tobacco dependence is associated with the emergence of negative emotional states during withdrawal, including anxiety and nociceptive hypersensitivity. However, the current animal models of nicotine dependence have focused on the mechanisms that mediate the acute reinforcing effects of nicotine and failed to link increased anxiety and pain during abstinence with excessive nicotine self-administration. Here, we tested the hypothesis that the activation of corticotropin-releasing factor-1 (CRF1 ) receptors and emergence of the affective and motivational effects of nicotine abstinence only occur in rats with long access (>21 hours/day, LgA) and not short (1 hour/day, ShA) access to nicotine self-administration. ShA and LgA rats were tested for anxiety-like behavior, nociceptive thresholds, somatic signs of withdrawal and nicotine intake after 3 days of abstinence. The role of CRF1 receptors during abstinence was tested using systemic or intracerebral infusion of MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5α)pyrimidin-7-amine), a CRF1 receptor antagonist, in the central nucleus of the amygdala (CeA). LgA but not ShA rats exhibited abstinence-induced increases in anxiety-like behavior and nociceptive hypersensitivity, which both predicted subsequent excessive nicotine intake and were prevented by systemic administration of MPZP. Intra-CeA MPZP infusion prevented abstinence-induced increases in nicotine intake and nociceptive hypersensitivity. These findings demonstrate that the model of short access to nicotine self-administration has limited validity for tobacco dependence, highlight the translational relevance of the model of extended-intermittent access to nicotine self-administration for tobacco dependence and demonstrate that activation of CRF1 receptors is required for the emergence of abstinence-induced anxiety-like behavior, hyperalgesia and excessive nicotine intake.
烟草依赖与戒断期间负面情绪状态的出现有关，包括焦虑和伤害性超敏反应。然而，目前的尼古丁依赖动物模型侧重于介导尼古丁急性强化作用的机制，未能将戒断期间焦虑和疼痛的增加与过量尼古丁自我给药联系起来。在此，我们检验了以下假设：促肾上腺皮质激素释放因子-1（CRF1）受体的激活以及尼古丁戒断的情感和动机效应仅在长期（>21小时/天，LgA）而非短期（1小时/天，ShA）获取尼古丁自我给药的大鼠中出现。对ShA和LgA大鼠在戒断3天后进行焦虑样行为、伤害性阈值、戒断体征和尼古丁摄入量测试。使用CRF1受体拮抗剂MPZP（N，N-双（2-甲氧基乙基）-3-（4-甲氧基-2-甲基苯基）-2，5-二甲基-吡唑并（1，5α）嘧啶-7-胺）通过全身或脑内注入杏仁核中央核（CeA）来测试CRF1受体在戒断期间的作用。LgA大鼠而非ShA大鼠表现出戒断诱导的焦虑样行为增加和伤害性超敏反应，这两者都预测了随后的过量尼古丁摄入，并且通过全身给予MPZP可预防。向CeA内注入MPZP可预防戒断诱导的尼古丁摄入量增加和伤害性超敏反应。这些发现表明，短期获取尼古丁自我给药模型对烟草依赖的有效性有限，突出了延长间歇性获取尼古丁自我给药模型对烟草依赖的转化相关性，并证明CRF1受体的激活是戒断诱导的焦虑样行为、痛觉过敏和过量尼古丁摄入出现所必需的。
