Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats
Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats
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DOI：
10.1038/sj.npp.1301192
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发表时间：
2007-04-01
影响因子：
7.6
通讯作者：
Gold, Mark S.
中科院分区：
文献类型：
--
作者：
Bruijnzeel, Adrie W.;Zislis, George;Gold, Mark S.
尼古丁依赖是一种慢性精神疾病，其特征是在戒烟后处于负面情绪状态，戒烟一段时间后又复发。有人假设，停止尼古丁给药会导致脑内促肾上腺皮质激素释放因子(CRF)系统的激活，从而导致戒断的负面情绪状态。我们实验的目的是研究脑CRF系统在大鼠停止尼古丁给药引起的大脑奖励功能缺陷中的作用。使用颅内自我刺激程序来评估尼古丁戒断的负面情感方面，因为这种程序可以提供对大鼠情绪痛苦的定量测量。在第一个实验中，甲氨基甲胺诱导尼古丁处理的大鼠大脑奖赏阈值随剂量的增加而升高。在后续实验中，发现用促肾上腺皮质激素受体拮抗剂D-Phe CRF(12-41)预处理可阻止与尼古丁催促戒断相关的大脑奖赏阈值的升高。在第三个实验中，研究了D-Phe CRF(12-41)对自发戒断尼古丁引起的脑奖赏阈值升高的影响。在尼古丁泵移植后6小时给予D-Phe CRF(12-41)，并不能降低大脑奖赏阈值。这些发现表明，CRF受体的拮抗作用可以预防，但不能逆转与尼古丁戒断相关的大脑缺陷。这些数据支持这样一种假设，即大脑CRF系统的过度活动可能至少部分地介导了尼古丁戒断的负面情感方面的启动。
Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF(12-41) prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF(12-41) on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF(12-41) 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal.