Moffett M C, Goeders N E
Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, LA 71130, USA.
Psychopharmacology (Berl). 2007 Feb;190(2):171-80. doi: 10.1007/s00213-006-0625-7. Epub 2006 Nov 21.
Previous studies from our laboratory and others have indicated a role for the hypothalamo-pituitary-adrenal (HPA) axis in the extinction/reinstatement animal model of cocaine relapse
This present study was designed to investigate the potential role for the HPA axis in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior by determining the effects of ketoconazole and the corticotropin-releasing hormone (CRF) type 1 receptor antagonist, CP-154,526, on these behaviors.
Male Wistar rats were trained to self-administer methamphetamine (0.03 mg/kg/infusion). The delivery of methamphetamine was paired with the presentation of a tone and the illumination of a house light. Once stable responding was reached, the rats were placed into extinction. The effects of pretreatment with ketoconazole (25, 50, or 100 mg/kg, i.p.) or CP-154,526 (20 or 40 mg/kg, i.p.; 3 micro g, i.c.v) on cue-induced reinstatement were then evaluated.
Cue-induced reinstatement was not significantly attenuated by pretreatment with peripherally administered CP-154,526 or by pretreatment with ketoconazole. However, centrally administered CP-154,526 (3 micro g, i.c.v.) significantly attenuated cue-induced reinstatement. In a separate group of rats, CP-154,526 (20 mg/kg, i.p.) attenuated methamphetamine-induced reinstatement (0.12 mg/kg priming infusion); whereas a higher dose (40 mg/kg) was necessary to attenuate reinstatement induced by a priming infusion of 0.24 mg/kg/infusion. Ketoconazole (50 mg/kg) did not affect reinstatement induced by a 0.12 mg/kg priming infusion and, therefore, was not tested at the higher methamphetamine priming dose.
These data suggest an important role for CRF in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior.
我们实验室及其他机构之前的研究表明，下丘脑-垂体-肾上腺（HPA）轴在可卡因复发的消退/复燃动物模型中发挥作用。
本研究旨在通过确定酮康唑和促肾上腺皮质激素释放激素（CRF）1型受体拮抗剂CP-154,526对这些行为的影响，来探究HPA轴在线索和甲基苯丙胺诱导的消退的甲基苯丙胺寻求行为复燃中的潜在作用。
雄性Wistar大鼠接受训练以自我给药甲基苯丙胺（0.03mg/kg/次注射）。甲基苯丙胺的给药与音调呈现和笼内灯光亮起配对。一旦达到稳定反应，大鼠即进入消退阶段。然后评估预先给予酮康唑（25、50或100mg/kg，腹腔注射）或CP-154,526（20或40mg/kg，腹腔注射；3μg，脑室内注射）对线索诱导复燃的影响。
外周给予CP-154,526预处理或酮康唑预处理均未显著减弱线索诱导的复燃。然而，脑室内注射CP-154,526（3μg）显著减弱了线索诱导的复燃。在另一组大鼠中，CP-154,526（20mg/kg，腹腔注射）减弱了甲基苯丙胺诱导的复燃（0.12mg/kg启动注射）；而对于0.24mg/kg/次注射的启动注射诱导复燃，需要更高剂量（40mg/kg）才能减弱。酮康唑（50mg/kg）不影响0.12mg/kg启动注射诱导的复燃，因此未在更高的甲基苯丙胺启动剂量下进行测试。
这些数据表明CRF在线索和甲基苯丙胺诱导的消退的甲基苯丙胺寻求行为复燃中起重要作用。
