Reich C G, Mohammadi M H, Alger B E
Department of Physiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Psychopharmacol. 2008 Sep;22(7):769-77. doi: 10.1177/0269881107083999. Epub 2008 Feb 28.
Recently, disruption of the endogenous cannabinoid (endocannabinoid, eCB) system was found to impair extinction in delay and contextual fear conditioning models. However, conditioning procedures used in that work precluded investigation of possible eCB effects on acquisition of learned fear. We therefore examined the role of eCBs in modulating fear responses using multiple-trial versions of trace (hippocampal-dependent) and delay (amygdala-dependent) Pavlovian fear conditioning. By administering the CB1 receptor antagonist AM251 (5 mg/kg, i.p) to C57/Bl/6 mice at various times, we systematically identified the stages of learning and memory (i.e. acquisition, consolidation, recall and extinction) that are modulated by eCB signaling. During tone (CS) - footshock (US) conditioning, AM251 enhanced acquisition of freezing behavior for both trace- and delay-conditioning protocols. CB1 antagonism also enhanced generalized fear (baseline freezing) and cued (CS) freezing during memory recall tests in a state-dependent manner for both trace and delay conditioned animals. Furthermore, in trace-conditioned animals, AM251 impaired extinction performance of both cued and generalized fear. CB1 antagonism did not affect short-term memory (STM) or long-term memory (LTM) consolidation processes. Together, these results suggest that during acquisition and recall of aversive learning, eCBs prevent the expression and retention of inappropriate generalized and learned responses. These findings have important implications for the therapeutic use of CB1 antagonists.
最近,研究发现内源性大麻素(eCB)系统的破坏会损害延迟和情境恐惧条件反射模型中的消退过程。然而,该研究中使用的条件反射程序排除了对eCB可能影响习得性恐惧获得的研究。因此,我们使用多次试验版本的痕迹(海马依赖性)和延迟(杏仁核依赖性)巴甫洛夫恐惧条件反射来研究eCB在调节恐惧反应中的作用。通过在不同时间给C57/Bl/6小鼠注射CB1受体拮抗剂AM251(5mg/kg,腹腔注射),我们系统地确定了受eCB信号调节的学习和记忆阶段(即获得、巩固、回忆和消退)。在音调(条件刺激,CS)-足部电击(非条件刺激,US)条件反射过程中,AM251增强了痕迹和延迟条件反射协议下冻结行为的获得。对于痕迹和延迟条件反射的动物,在记忆回忆测试中,CB1拮抗作用还以状态依赖的方式增强了广义恐惧(基线冻结)和线索(CS)诱导的冻结。此外,在痕迹条件反射的动物中,AM251损害了线索恐惧和广义恐惧的消退表现。CB1拮抗作用不影响短期记忆(STM)或长期记忆(LTM)的巩固过程。总之,这些结果表明,在厌恶学习的获得和回忆过程中,eCB可防止不适当的广义和习得反应的表达和保留。这些发现对CB1拮抗剂的治疗应用具有重要意义。