Basso A M, Spina M, Rivier J, Vale W, Koob G F
Department of Neuropharmacology CVN-7, La Jolla, CA 92037, USA.
Psychopharmacology (Berl). 1999 Jul;145(1):21-30. doi: 10.1007/s002130051028.
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.
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.
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 [DPhe12, Nle21,38, CalphaMe Leu37] r/h CRF(12-41), (also known as D-phe CRF(12-41)) (0.04, 0.2 and 1.0 microg/5 microl) was injected 5 min before the 15-min testing.
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.
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.
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，众所周知可调节应激反应。据推测，CRF参与了慢性给药后可卡因戒断相关的焦虑和/或应激反应的神经生物学机制。
本研究使用防御性埋埋范式和高架十字迷宫，研究内源性CRF在介导大鼠停止生理盐水或慢性可卡因治疗48小时后的“焦虑样”效应中的作用。
大鼠每日注射可卡因（20mg/kg腹腔注射，连续14天）或溶剂。最后一次注射后48小时，动物先在十字迷宫中进行测试，然后在防御性埋埋范式中进行测试。在第二个实验中，将脑室内（ICV）套管植入侧脑室。在开始慢性药物治疗前，让动物恢复1周。治疗停止48小时后进行防御性埋埋测试。在15分钟测试前5分钟，注射CRF拮抗剂[DPhe12，Nle21,38，CalphaMe Leu37]r/h CRF(12 - 41)（也称为D - phe CRF(12 - 41)）（0.04、0.2和1.0μg/5μl）。
慢性可卡因治疗后，防御性埋埋范式显示出“焦虑样”效应，但高架十字迷宫未显示。这种“焦虑样”反应通过ICV预处理CRF拮抗剂D - Phe CRF(12 - 41)而减弱，最高剂量的CRF拮抗剂可逆转观察到的“焦虑样”反应。
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“焦虑样”反应的发展，并且可能对未来的药物依赖治疗很重要。
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