Differential response to acute and repeated stress in cannabinoid CB1 receptor knockout newborn and adult mice

Previous studies have suggested that the endocannabinoid CB(1) receptor (ECBR) system is involved in stress. However, the nature of this association is complex. Here, we investigated the role of CB(1) receptors in the response to stress by comparing the effects of various stress modalities in CB(1)(-/-) receptor deficient and wild-type mice, at adulthood and during early development. Response to acute stress was assayed by plasma corticosterone (CS) and adrenocorticotrophic hormone (ACTH), USVs and motor inhibition. The response to repeated stress was assessed by USVs and motor inhibition. Since repeated bell stress seemed to cause a cumulative fear in CB(1) receptor knockout mice, these behavioral responses were also compared to those observed after a single severe stress (forced swimming). In wild-type, but not in CB(1) receptor knockout mice, bell stress-induced elevations of ACTH and CS were significant. The first exposure to bell stress had no significant effect on USVs or mobility. Upon repeated exposures, significant suppression of USVs, together with behavioral inhibition, were observed in CB(1) knockout but not in wild-type mice. Swim stress inhibited USVs in the knockout animals, and the profound motor inhibition displayed by all animals was greater and more prolonged in the CB(1)(-/-) mice. Since the knockout mice lack the CB(1) receptor throughout pre- and postnatal life, the stress response in pups was also assayed (by separation-induced USVs). Wild-type pups displayed the characteristic developmental peak in USV emissions; it was completely lacking in knockout pups. We conclude that acutely, the absence of CB(1) receptors reduces the neuroendocrine response and does not affect the behavioral response to moderate stress. However, upon repeated stress or acute severe stress, CB(1) receptor deficiency causes persistent behavioral inhibition. Finally, the CB(1) receptor plays a role in modulating the stress response from an early age. These observations suggest that CB(1) receptors participate in the mediation of the stress response and that the absence of these receptors results in a greater vulnerability to stress. We suggest that the stress-induced endocrine and behavioral suppression in CB(1) receptor deficient mice may serve as a model for some forms of post-traumatic stress disorder (PTSD). Further, the role of CB(1) receptors in coping with stress is a lifelong function. Finally, although equivalent research has not been performed in human infants, the postnatal suppression of the stress response in CB(1) receptor knockout pups may have implications when cannabinoid-based therapy is considered for children.