Corticotropin-releasing factor antagonist attenuates the "anxiogenic-like" effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats
Corticotropin-releasing factor antagonist attenuates the "anxiogenic-like" effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats
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DOI：
10.1007/s002130051028
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发表时间：
1999-07-01
影响因子：
3.4
通讯作者：
Koob, GF
中科院分区：
文献类型：
--
作者：
Basso, AM;Spina, M;Koob, GF
理论基础：慢性可卡因滥用与人类焦虑状态的发展有关。促肾上腺皮质激素释放因子(CRF)是一种内源性神经营养因子，可调节应激反应。据推测，CRF参与了慢性给药后与戒除可卡因相关的焦虑和/或应激反应的神经生物学机制。目的：采用防御掩埋实验和高架正迷宫实验，探讨内源性促肾上腺皮质激素释放因子(CRF)在大鼠停用生理盐水或慢性可卡因48h后的“焦虑样”效应中的作用。方法：大鼠每日注射可卡因(20 mg/kg，连续14天)或溶媒。在最后一次注射48小时后，动物在加迷宫中接受测试，然后在防御性掩埋范例中进行测试。在第二个实验中，在侧脑室植入脑室内(ICV)套管。在开始慢性药物治疗之前，动物被允许有一周的恢复期。防御性埋葬试验在停药后48h进行。在15min测试前5min注射CRF拮抗剂[DPhe(12)，NLE(21，38)，(CME)-Me-Alpha Leu(37)]r/h CRF(12-41)，(又称D-Phe CRF(12-41))(0.04，0.2，1.0ug/5亩L)。结果：在防御性掩埋模式下，慢性可卡因治疗后表现出“类焦虑”效应，而在高架的正迷宫中则没有。这种“焦虑样”反应可通过脑室注射CRF拮抗剂D-Phe CRF(12-41)来减弱，其中最高剂量的CRF拮抗剂可逆转观察到的“焦虑样”反应。结论：这些数据表明，脑CRF可能在很大程度上参与了与可卡因戒断相关的“类焦虑”反应的发展，并可能对未来的药物依赖治疗具有重要意义。
Rationale: Chronic cocaine abuse is associated with the development of anxiogenic states in humans. Corticotropin-releasing factor (CRF) is an endogenous neurotropic factor well known to modulate stress responses. It has been postulated that CRF is involved in the neurobiological mechanisms underlying the anxiety and/or stress responses associated with removal of cocaine after chronic administration. Objective: The present study investigated the role of endogenous CRF in mediating the "anxiety-like" effect 48 h after the cessation of saline or chronic cocaine treatment in rats, using the defensive burying paradigm and the elevated plus-maze. Methods: Rats received daily injections of cocaine (20 mg/kg IP, for 14 consecutive days) or vehicle. Forty-eight hours after the last injection, animals were tested in the plus-maze and then in the defensive burying paradigm. In a second experiment, intracerebroventricular (ICV) cannulae were implanted at the lateral ventricle. Animals were allowed a 1-week period for recovery before starting the chronic drug treatment. The defensive burying testing took place 48 h after cessation of the treatment. The CRF antagonist [DPhe(12), Nle(21,38), (CMe)-Me-alpha Leu(37)] r/h CRF(12-41), (also known as D-phe CRF(12-41)) (0.04, 0.2 and 1.0 mu g/5 mu l) was injected 5 min before the 15-min testing. Results: An "anxiogenic-like" effect following chronic cocaine treatment was demonstrated with the defensive burying paradigm, but not with the elevated plus-maze. This "anxiety-like" response was attenuated by ICV pretreatment with the CRF antagonist D-Phe CRF(12-41), with the highest dose of the CRF antagonist reversing the observed "anxiogenic-like" response. Conclusions: These data suggest that brain CRF may be substantially involved in the development of "anxiety-like" responses related to cocaine withdrawal and could be important for future drug dependence treatments.