Proc Natl Acad Sci U S A. 2016 Aug 15. pii: 201525066. [Epub ahead of print]
Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation.
Busquets-Garcia A1, Gomis-González M2, Srivastava RK3, Cutando L2, Ortega-Alvaro A2, Ruehle S3, Remmers F3, Bindila L3, Bellocchio L4, Marsicano G4, Lutz B3, Maldonado R2, Ozaita A5.
1Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain; Endocannabinoids and Neuroadaptation Group, NeuroCentre Magendie, INSERM U1215, 33077, Bordeaux, France;
2Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain;
3Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
4Endocannabinoids and Neuroadaptation Group, NeuroCentre Magendie, INSERM U1215, 33077, Bordeaux, France;
5Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain; andres.ozaita@upf.edu.
Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine ß-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH+ cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.
PLoS One. 2016 Aug 8;11(8):e0160462. doi: 10.1371/journal.pone.0160462. eCollection 2016.
Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1 (CB1) Are Neither Obese Nor Diabetic.
Marcus DJ1,2,3, Zee ML3, Davis BJ1,2, Haskins CP1,2,3, Andrews MJ1,2,4, Amin R1,2,4, Henderson-Redmond AN3, Mackie K1,2,4, Czyzyk TA3, Morgan DJ1,2,3,4.
1Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, 47405,United States of America.
2Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, 47405, United States of America.
3Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania, 17033, United States of America.
4Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, 47405, United States of America.
Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization-resistant CB1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45%) and low fat (10%) chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild-type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast. |
