Pitman Roger K, Milad Mohammed R, Igoe Sarah A, Vangel Mark G, Orr Scott P, Tsareva Alina, Gamache Karine, Nader Karim
Department of Psychiatry, Massachusetts General Hospital, MGH-East, 120 Second Avenue, Charlestown, MA 02129, USA.
Behav Neurosci. 2011 Aug;125(4):632-8. doi: 10.1037/a0024364.
Reducing reconsolidation of reactivated traumatic memories may offer a novel pharmacological treatment for posttraumatic stress disorder (PTSD). Preclinical research is needed to identify candidate drugs. We evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats. On Day 1, a 30-s tone conditioned stimulus (CS) was paired with an electric shock unconditioned stimulus (US). On Day 2, the CS was presented without the US (reactivation), and the freezing conditioned response (CR) was measured. This was immediately followed by subcutaneous injection of vehicle, mifepristone 30 mg/kg, propranolol 10 mg/kg, or both. On Day 3, the CR was again measured as a test of postreactivation long-term memory (PR-LTM). On Day 10, the CR was again measured to evaluate spontaneous recovery. On Day 11, the US was presented alone (reinstatement). On Day 12, the CR was again measured. A fifth group received mifepristone without the CS presentation (nonreactivation) on Day 2. A sixth group was tested four hours after the Day 2 mifepristone injection to measure postreactivation short-term memory. Postreactivation, but not nonreactivation, mifepristone produced a decrement in the CR that did not undergo spontaneous recovery and underwent only modest reinstatement. Mifepristone did not exert its effect when administered concurrently with propranolol. Postreactivation mifepristone did not impair short-term memory. Systemic mifepristone blocks the reconsolidation of cue-conditioned fear in rats. Concurrent administration of propranolol prevents this effect. Postreactivation mifepristone may be a promising treatment for PTSD, but not necessarily in combination with propranolol.
减少重新激活的创伤性记忆的再巩固可能为创伤后应激障碍（PTSD）提供一种新的药物治疗方法。需要进行临床前研究以确定候选药物。我们评估了系统给予的再激活后米非司酮（RU38486，一种糖皮质激素拮抗剂）单独使用以及与普萘洛尔（一种β-肾上腺素能阻滞剂）联合使用对降低大鼠线索条件性恐惧的能力。在第1天，一个30秒的纯音条件刺激（CS）与电击非条件刺激（US）配对。在第2天，呈现CS但不给予US（重新激活），并测量冻结条件反应（CR）。随后立即皮下注射赋形剂、30mg/kg米非司酮、10mg/kg普萘洛尔或两者。在第3天，再次测量CR作为再激活后长期记忆（PR-LTM）的测试。在第10天，再次测量CR以评估自发恢复。在第11天，单独呈现US（恢复）。在第12天，再次测量CR。第五组在第2天接受米非司酮但不呈现CS（未重新激活）。第六组在第2天米非司酮注射后4小时进行测试以测量再激活后短期记忆。再激活后而非未激活时，米非司酮使CR减少，该减少未经历自发恢复且仅经历适度恢复。米非司酮与普萘洛尔同时给药时不发挥其作用。再激活后米非司酮不损害短期记忆。全身给予米非司酮可阻断大鼠线索条件性恐惧的再巩固。普萘洛尔同时给药可防止这种作用。再激活后米非司酮可能是一种有前景的PTSD治疗方法，但不一定与普萘洛尔联合使用。
