Role of the endocannabinoid system in extinction of fear memories: lessons from animal studies

Abstract

Rationale : Generalized avoidance belongs to the core symptoms of a variety of anxiety disorders such as panic disorder or posttraumatic stress disorder. However, therapy for avoidance behavior still bears many obstacles. Even though exposure-based approaches are the method of choice, they suffer from inferior patient compliance. This can be ascribed to patients’ inability to stand the high emotional load experienced during the therapeutic sessions. The situation could be much improved if (1) learning about the safety of a feared situation could be enforced, while (2) the negative effect inherent to the exposure is decreased. This would allow for the number/duration of the exposure sessions to be restricted to a minimum, and at the same time, the emotional load of the therapeutic sessions could be dampened, with direct consequences on compliance rates. So far, however, most of the treatments with anxiolytic capabilities (e.g., benzodiazepines) lead to state-dependency or amnesia, with the consequence that safety learning is attenuated, if not completely blocked. Methods : The role of the endocannabinoid system in fear relief and safety learning was investigated in numerous animal studies employing pharmacological and genetic approaches. Behavioral experiments involved classical fear conditioning and inhibitory avoidance learning, followed by extinction training and safety learning. Mice were treated with the CB1 receptor antagonist/inverse agonist SR141716 (3 mg/kg) or the endocannabinoid uptake/degradation inhibitor AM404 (3 mg/kg). Parts of the experiments were performed with conventional and conditional mice lacking expression of CB1 receptors either in the entire brain or in distinct neuronal populations. Results : Our studies revealed the following key findings: (1) Endocannabinoids play an essential role in acute fear relief, once the averseness of the test situation exceeded a certain threshold. (2) These effects are mediated via CB1 on glutamatergic nerve terminals. (3) The capacity of the endocannabinoid system is limited in highly aversive situations but can be reestablished by blocking of endocannabinoid uptake/degradation. (4) At the same time, signaling via CB1 on dopamine D1 receptor positive neurons contributes not only to acute fear relief but also to safety learning in an inhibitory avoidance task. (5) The efficiency of safety learning in this task can be improved and the risk of relapse of avoidance behavior can be reduced by pharmacological enhancement of endocannabinoid signaling. Conclusion : Drugs promoting endocannabinoid signaling via CB1 receptors may represent a new class of compounds that combine the advantages of “happy pills” (in terms of fear and stress relief) with those of “smart drugs” (i.e., facilitated safety learning), thus increasing compliance rates and success of exposure-based therapies in anxiety disorders.

Keywords

• endocannabinoid
• fear extinction
• CB1 receptor
• exposure therapy
• safety learning