Lê A D, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y
Department of Neuroscience, Center for Addiction and Mental Health, Toronto, Ontario, Canada.
Psychopharmacology (Berl). 2000 Jun;150(3):317-24. doi: 10.1007/s002130000411.
Intermittent footshock stress reliably reinstates extinguished alcohol-taking behavior in drug-free rats, but the neurochemical events involved in this effect are not known.
We studied here whether two main modulators of stress responses, corticotropin-releasing factor (CRF) and corticosterone, are involved in reinstatement of alcohol seeking induced by the intermittent footshock stressor. METHDOS: Rats were given alcohol in a two-bottle choice procedure (water versus alcohol) for 30 days and were then trained for 60 min per day to press a lever for alcohol (12% w/v) for 24-30 days in operant conditioning chambers. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 5-8 days. Reinstatement of alcohol seeking was then determined after exposure to intermittent footshock (0.8 mA; 10 min) in different groups of rats that were pretreated with CRF receptor antagonists or underwent adrenalectomy (ADX) to remove endogenous corticosterone from the body.
The CRF receptor antagonists, d-phe-CRF (0.3 or 1.0 microg; ICV) and CP-154,526 (15, 30 or 45 mg/kg; IP) attenuated footshock-induced reinstatement of alcohol seeking in a dose dependent manner. In contrast, the removal of circulating corticosterone by ADX had no effect on footshock stress-induced reinstatement of alcohol-taking behavior. In addition, the prevention of the footshock-induced rise in corticosterone while maintaining basal levels of the hormone by providing adrenalectomized rats with corticosterone pellets (50 mg/kg per day), had no effect on stress-induced reinstatement.
These data suggest that CRF contributes to stress-induced relapse to alcohol seeking via its actions on extra-hypothalamic sites. The present data, and previous data with heroin- and cocaine-trained rats, point to a general role of CRF in relapse to drugs induced by stressors.
间歇性足部电击应激能可靠地恢复无药物大鼠已消退的酒精摄取行为，但此效应所涉及的神经化学事件尚不清楚。
我们在此研究应激反应的两种主要调节因子，促肾上腺皮质激素释放因子（CRF）和皮质酮，是否参与间歇性足部电击应激源诱导的酒精觅求行为的恢复。方法：大鼠在双瓶选择程序（水与酒精）中给予酒精30天，然后每天在操作性条件反射箱中训练60分钟按压杠杆以获取酒精（12%重量/体积），持续24 - 30天。在获得稳定的药物摄取行为后，通过终止药物递送5 - 8天来消除按压杠杆获取酒精的行为。然后在不同组的大鼠中，在给予CRF受体拮抗剂预处理或进行肾上腺切除术（ADX）以去除体内内源性皮质酮后，暴露于间歇性足部电击（0.8 mA；10分钟）后，确定酒精觅求行为的恢复情况。
CRF受体拮抗剂，d - 苯丙氨酸 - CRF（0.3或1.0微克；脑室内注射）和CP - 154,526（15、30或45毫克/千克；腹腔注射）以剂量依赖性方式减弱足部电击诱导的酒精觅求行为的恢复。相反，通过ADX去除循环皮质酮对足部电击应激诱导的酒精摄取行为的恢复没有影响。此外，通过给肾上腺切除的大鼠提供皮质酮丸剂（每天50毫克/千克）来防止足部电击诱导的皮质酮升高，同时维持激素的基础水平，对应激诱导的恢复没有影响。
这些数据表明CRF通过其对下丘脑外部位的作用促进应激诱导的酒精觅求行为复发。目前的数据以及先前对海洛因和可卡因训练大鼠的数据表明，CRF在应激源诱导的药物复发中起普遍作用。
