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dc.contributor.authorNavia-Paldanius, Dina
dc.contributor.authorAaltonen, Niina
dc.contributor.authorLehtonen, Marko
dc.contributor.authorSavinainen, Juha R.
dc.contributor.authorTaschler, Ulrike
dc.contributor.authorRadner, Franz P.W.
dc.contributor.authorZimmermann, Robert
dc.contributor.authorLaitinen, Jarmo T.
dc.date.accessioned2016-06-21T05:45:04Z
dc.date.available2016-06-21T05:45:04Z
dc.date.issued2015-09-18
dc.identifier10.1016/j.ejps.2015.06.005
dc.identifier.citationNavia-Paldanius, Dina, Aaltonen, Niina, Lehtonen, Marko, Savinainen, Juha R., Taschler, Ulrike, Radner, Franz P.W., Zimmermann, Robert, Laitinen, Jarmo T. 2015. ncreased tonic cannabinoid CB1R activity and brain region-specific desensitization of CB1R Gi/o signaling axis in mice with global genetic knockout of monoacylglycerol lipase. European Journal of Pharmaceutical Sciences Vol.: 77. Elsevier BV. Doi: 10.1016/j.ejps.2015.06.005. Issn: 0928-0987.fi_FI
dc.identifier.issn0928-0987
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/98
dc.descriptionArticle
dc.description.abstractIn mammalian brain, monoacylglycerol lipase (MAGL) is the primary enzyme responsible for terminating signaling function of the endocannabinoid 2-arachidonoylglycerol (2-AG). Previous in vivo studies with mice indicate that both genetic and chronic pharmacological inactivation of MAGL result in 8–30-fold increase of 2-AG concentration in the brain, causing desensitization and downregulation of cannabinoid CB1 receptor (CB1R) activity, leading to functional and behavioral tolerance. However, direct evidence for reduced CB1R activity in the brain is lacking. In this study, we used functional autoradiography to assess basal and agonist-stimulated CB1R-dependent Gi/o protein activity in multiple brain regions of MAGL-KO mice in comparison to their wild-type (WT) littermates. In addition, the role of endogenous cannabinoids in basal CB1R signaling was assessed after comprehensive pharmacological blockade of 2-AG hydrolysis by determining the contents of endocannabinoids (eCBs) in WT and MAGL-KO brain tissues by LC/MS/MS technology. To show whether lack of MAGL cause compensatory alterations in the serine hydrolase activity, we compared serine hydrolase pattern of WT and MAGL-KO using activity-based protein profiling. Consistent with studies using chronic pharmacological MAGL inactivation in vivo, we observed a statistically significant decrease of CB1R-Gi/o signaling in most of the studied brain regions. In MAGL-KO brain sections, elevated 2-AG levels were mirrored to heightened basal CB1R-dependent Gi/o-activity, as well as, dampened agonist-evoked responses in several brain regions. The non-selective serine hydrolase inhibitor methylarachidonoylfluorophosphonate (MAFP) was able to significantly elevate 2-AG levels in brain sections of MAGL-KO mice, indicating that additional serine hydrolases possess 2-AG hydrolytic activity in MAGL-KO brain sections.fi_FI
dc.language.isoenfi_FI
dc.publisherElsevier BVfi_FI
dc.relation.ispartofseriesEuropean Journal of Pharmaceutical Sciences 77;
dc.relation.urihttp://dx.doi.org/10.1016/j.ejps.2015.06.005
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMonoacylglycerol lipase-knockoutfi_FI
dc.subject[35S]GTPγS autoradiographyfi_FI
dc.subjectDesensitizationfi_FI
dc.subject2-arachidonoylglycerolfi_FI
dc.subjectEndocannabinoidfi_FI
dc.subjectCannabinoid CB1 receptorfi_FI
dc.titleIncreased tonic cannabinoid CB1R activity and brain region-specific desensitization of CB1R Gi/o signaling axis in mice with global genetic knockout of monoacylglycerol lipasefi_FI
dc.typehttp://purl.org/eprint/type/JournalArticle
dc.description.versionFinal Draft
uef.solecris.id33358709
eprint.statushttp://purl.org/eprint/status/PeerReviewed
dc.type.publicationinfo:eu-repo/semantics/article
dc.rights.accessrights© Elsevier B.V.
dc.relation.doi10.1016/j.ejps.2015.06.005
dc.description.reviewstatushttp://purl.org/eprint/status/PeerReviewed
dc.relation.issn0928-0987
dc.rights.accesslevelopenAccess


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