Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity

Abstract

Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light-dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long-term potentiation (LTP) in the CA1, (iii) impaired hippocampal-dependent short-term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala-dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55-212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal- and amygdala-dependent processes. Moreover, the effects of WIN55-212,2 and URB597 on Ext and acoustic startle were prevented by co-administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55-212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala.

Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity

“…and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg, i.p.) 2 h after shock exposure [6]. We found that cannabinoids administered in the aftermath of trauma can prevent the development of PTSD-like behaviors [2,7].…”

“…Behavioral metaplasticity involves altered plasticity at the level of the neural systems following exposure to stress. We have shown that exposure to shock and reminders induced metaplasticity in the CA1 and BLA [6].…”

“…URB597 (0.3 mg/kg) prevents AEA inactivation by targeting the intracellular enzymatic activity of FAAH (inhibits FAAH activity with an ID50 value of 0.15 mg kg after systemic administration in the rat [10]). Moreover, URB597 was found to trigger active coping behavior [11], and to prevent the effects of exposure to shock and reminders in a rat model of PTSD on depressive-and anxiety-like behaviors [6,12]. Intra-BLA URB597 facilitated extinction and attenuated startle response following shock and reminders [13], and decreased anxiety under conditions of low emotional arousal [14].…”

“…The amygdala and hippocampus are brain regions involved in fear and memory and are highly implicated in PTSD. We have recently shown that exposure to the shock and reminders model of PTSD had opposing effects on hippocampal-and amygdaladependent processes: hippocampal plasticity and spatial memory were impaired, whereas amygdala plasticity and conditioned taste aversion enhanced [6]. These opposing effects were prevented by administering the CB1/2 receptor agonist WIN55-212,2 (0.5 mg/kg, i.p.)…”

“…Hence in the current study, we aimed to examine whether administrating URB597 before extinction will attenuate fear and facilitate extinction in the BLA and CA1. We used URB597 as it was shown to have antianxiety and antidepressant-like effects in different models [6,8,9]. URB597 (0.3 mg/kg) prevents AEA inactivation by targeting the intracellular enzymatic activity of FAAH (inhibits FAAH activity with an ID50 value of 0.15 mg kg after systemic administration in the rat [10]).…”