A differential role for the endocannabinoids anandamide and 2-arachidonoylglycerol in modulating the retrieval of cued- and contextual- fear memory

Dysfunctional processes in memory retrieval could be answerable for altered emotional responses and for the development of neuropsychiatric disorders, such as Post-traumatic stress disorder. The endocannabinoid system plays a crucial role in the regulation of memory functions and emotional responses. However, if much has been learned about its engagement in memory acquisition and memory consolidation, evidence on the role of the endocannabinoid system in the retrieval of memory for traumatic experiences are still limited. Here, we investigated the effects induced by pharmacological manipulation of the endocannabinoid signalling in the dorsal hippocampus or in the basolateral complex of the amygdala (BLA) on memory retrieval of fearful events. To this aim, adult male Sprague Dawley rats were trained in a Contextual or Auditory Fear Conditioning task. Sixty minutes before retrieval, they were bilaterally infused, into the BLA or into the dorsal CA1 sub-region of the hippocampus with the FAAH inhibitor, URB597, or the MAGL inhibitor, KML29, in order to increase endogenous levels of anandamide and 2-arachinoyglycerol (2-AG), respectively. We found that, depending on the brain areas committed to encoding the reminder values, anandamide and 2-AG differentially impaired retrieval of aversive memories. We provide evidence that the endogenous cannabinoids anandamide and 2-AG are a key players in regulating fear memory retrieval, opening the way to new potential therapeutic target for the treatment of behavioural disorders where a previous exposure to traumatic events could alter the response to trauma reminder leading to mental illness and neuropsychiatric disorders.