Cannabinoid CB1 Receptor Mediates Fear Extinction via Habituation-Like Processes

Abstract

The interplay between fear expression and fear extinction provides an important prerequisite for adequate coping with aversive encounters. Current models propose that extinction of conditioned fear is mediated by associative safety learning. Here, we demonstrate that the cannabinoid CB1 receptor, which is crucially involved in fear extinction, is dispensable for associative safety learning. In fact, our results indicate that CB1 mediates fear extinction primarily via habituation-like processes. CB1 null-mutant mice were severely impaired not only in extinction of the fear response to a tone after fear conditioning but also in habituation of the fear response to a tone after sensitization with an inescapable footshock. Surprisingly, long-term habituation was generally affected even in situations with proper short-term adaptation, suggesting the existence of two separated CB1-dependent effector systems for short-and long-term fear adaptation. Our findings underscore the importance of habituation as a determinant of fear extinction in mice and characterize the cannabinoid CB1 receptor as an essential molecular correlate of this process.

Mechanisms of fear extinction

“…There are a number of respects in which the 'sensitization' phenomenon reported by Kamprath et al 55,237 runs counter to what would be expected based on a classical conception of sensitization. For example, sensitized freezing occurs even at a long delay after footshock exposure (in one case, as long as 1 month 237 ), and is mitigated by pre-exposure to the tone before footshock, a phenomenon reminiscent of latent inhibition.…”

“…Groves and Thompson 238 ). In their more recent paper, Kamprath et al 237 demonstrate that sensitized CB1À/À mice and mice treated with the CB1 antagonist SR141716A show deficits in within-session habituation of freezing that parallel very closely the deficits that these animals show in within-session extinction, 233 and on this basis they argue that cannabinoids are involved in a general habituation process of which extinction is one example.…”

“…It has been suggested that the apparent facilitation of extinction by cannabinoid agonists or reuptake inhibitors is in fact due to an impairment of memory reconsolidation by these compounds, 236 although it is somewhat difficult to compare this study to that of Chhatwal 234 because of the different routes of administration employed (systemic vs intra-amygdala) as well as the finding of a significant effect of WIN 55,21202 in one case 236 and not the in other. 234 Kamprath et al 237 have argued that endogenous cannabinoids modulate nonassociative learning processes including habituation, and are involved in fear extinction only to the extent that habituation is a component of extinction. That is, endogenous cannabinoid release is not a mechanism of fear extinction per se but rather occurs under conditions in which habituation occurs, which include, but are not specific to, extinction.…”

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

“…For instance, the importance of endocannabinoid signaling for the extinction of aversive memories was recently demonstrated in our laboratory. 8,9 Endocannabinoid signaling seems to be indispensable for the adequate coping of the organism with aversive and stressful situations. These findings fit well with the observations that pharmacologically increased endocannabinoid signaling exerts anxiolytic effects in rodents 10,11 and, thus, could represent an important lead for the development of new anti-anxiety drugs.…”

“…19 Given the high comorbidity between anxiety and major depression, 20 recent research has also focused on a potential role of the endocannabinoid system in the pathology of major depression 13,21 particularly of the melancholic subtype. 13 CB1 receptor-deficient mice share several symptoms with patients suffering from melancholic depression such as, for example, altered responsiveness to reward stimuli, 22 altered neurovegetative functions, 23 a predominance and persistence of aversive memories, 8,9 and possibly neurodegeneration. 24 Furthermore, it was shown by us and others that impaired endocannabinoid signaling can lead to sustained hyperreactivity of the hypothalamic-pituitaryadrenocortical (HPA) axis 23,25 and might also interfere with the proliferation of neural progenitor cells.…”