Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch Sasebo, Nagasaki 859-3298, Japan.
Pharmacol Biochem Behav. 2012 Apr;101(2):297-302. doi: 10.1016/j.pbb.2012.01.003. Epub 2012 Jan 12.
Recent evidence suggests the involvement of corticotropin-releasing factor (CRF) in drug abuse. Here, we evaluated whether CRF modulates the reinstatement of methamphetamine (METH)-seeking behavior induced by stress using a drug-self administration paradigm in rats. Rats were trained to lever-press for intravenous METH (0.02 mg/infusion) accompanied by light and tone (drug-associated cues) and then underwent extinction training (saline substituted for METH without cues). Under the extinction condition, the inhibitory effects of a CRF receptor antagonist on the stress-induced reinstatement of METH-seeking behavior were assessed. Anxiety-like behaviors during METH withdrawal in METH self-administered rats were also evaluated. The non-selective CRF receptor antagonist α-helical CRF(9-41) attenuated METH-seeking behavior induced by footshock stress. CRF levels both in the amygdala and in plasma were significantly increased on day 10 of withdrawal after METH self-administration. However, plasma corticosterone concentrations were unchanged during the withdrawal. In addition, METH-seeking behavior was not affected by an inhibitor of corticosterone synthesis, metyrapone. In the elevated plus maze test, METH self-administered rats showed a decrease in the duration of time spent in the open arms on day 10 of withdrawal. The increased CRF levels in the amygdala may, at least in part, contribute to the footshock-induced reinstatement of METH-seeking behavior and the increase in anxiety-like behavior. The present findings indicate that CRF receptor antagonists would be useful as a therapeutic agent for METH-dependence.
最近的证据表明，促肾上腺皮质素释放因子（CRF）参与了药物滥用。在这里，我们使用大鼠药物自我给药范式评估了 CRF 是否调节应激引起的甲基苯丙胺（METH）寻求行为的复燃。大鼠接受训练以通过静脉内 METH（0.02mg/ 输注）按压杠杆，同时伴有光和音（药物相关线索），然后进行消退训练（用盐水代替没有线索的 METH）。在消退条件下，评估了 CRF 受体拮抗剂对应激诱导的 METH 寻求行为复燃的抑制作用。还评估了 METH 自我给药大鼠 METH 戒断期间的焦虑样行为。非选择性 CRF 受体拮抗剂α-螺旋 CRF（9-41）减弱了足部电击应激引起的 METH 寻求行为。METH 自我给药后第 10 天，杏仁核和血浆中的 CRF 水平显着升高。然而，在戒断期间，血浆皮质酮浓度不变。此外，皮质酮合成抑制剂甲吡酮对 METH 寻求行为没有影响。在高架十字迷宫测试中，METH 自我给药大鼠在戒断第 10 天显示出在开放臂上花费的时间减少。杏仁核中 CRF 水平的升高至少部分导致了足部电击诱导的 METH 寻求行为的复燃和焦虑样行为的增加。本研究结果表明，CRF 受体拮抗剂可能是治疗 METH 依赖的有效药物。
