title: Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.
abstract: Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 μg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing.
  
  
  CONCLUSIONS
  Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy, Hotchkiss Brain Institute and Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Alberta T2N 4N1, Canada, maria.morena@uniroma1.it patrizia.campolongo@uniroma1.it.
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0001-6590-8130
authors.initials: M
authors.lastname: Morena
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: De Castro
authors.affiliation: Hotchkiss Brain Institute and Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: J Megan
authors.initials: JM
authors.lastname: Gray
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Palmery
authors.affiliation: Department of Science, Section of Biomedical Sciences and Technologies, University Roma Tre, 00146 Rome, Italy, and.
authors.forename: Viviana
authors.initials: V
authors.lastname: Trezza
authors.affiliation: Department of Cognitive Neuroscience, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Roozendaal
authors.affiliation: Hotchkiss Brain Institute and Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Hill
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy, maria.morena@uniroma1.it patrizia.campolongo@uniroma1.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Campolongo
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000097:blood / Q000378:metabolism; D013696:Temperature
chemical_list: D001095:Arachidonic Acids; D001549:Benzamides; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063386:Cannabinoid Receptor Agonists; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D009025:Morpholines; D009281:Naphthalenes; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D003345:Corticosterone
keywords: cannabinoid receptors; emotional arousal; endocannabinoids; memory for emotional experiences; stress