{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:59:24Z","timestamp":1792677564460,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,9,11]],"date-time":"2015-09-11T00:00:00Z","timestamp":1441929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Intramural Foundings of the Endocannabinoid Research Group at Institute of Biomolecular Chemistry of CNR of Pozzuoli"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2015,11]]},"abstract":"Abstract<\/jats:title>\n \n \n \n Endocannabinoids (\n eCB<\/jats:styled-content>\n ) are key regulators of excitatory\/inhibitory neurotransmission at cannabinoid\u20101\u2010receptor (\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R)\u2010expressing axon terminals. The most abundant\n eCB<\/jats:styled-content>\n in the brain, that is 2\u2010arachidonoylglycerol (2\u2010\n AG<\/jats:styled-content>\n ), is hydrolyzed by the enzyme monoacylglycerol lipase (\n MAGL<\/jats:styled-content>\n ), whose chronic inhibition in the brain was reported to cause\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R desensitization. We employed the\n MAGL<\/jats:styled-content>\n knock\u2010out mouse (\n MAGL<\/jats:styled-content>\n \u2212\/\u2212), a genetic model of congenital and sustained elevation of 2\u2010\n AG<\/jats:styled-content>\n levels in the brain, to provide morphological and biochemical evidence for \u03b2\u2010arrestin2\u2010mediated\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R desensitization in brain regions involved in the control of emotional states, that is, the prefrontal cortex (\n PFC<\/jats:styled-content>\n ), amygdala, hippocampus and cerebellar cortex. We found a widespread\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R\/\u03b2\u2010arrestin2 co\u2010expression in the\n mPFC<\/jats:styled-content>\n , amygdala and hippocampus accompanied by impairment of extracellular signal\u2010regulated kinase signaling and elevation of vesicular glutamate transporter (\n VG<\/jats:styled-content>\n luT1) at\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R\u2010positive excitatory terminals in the\n mPFC<\/jats:styled-content>\n , or vesicular\n GABA<\/jats:styled-content>\n transporter (\n VGAT<\/jats:styled-content>\n ) at\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R\u2010positive inhibitory terminals in the amygdala and hippocampus. The impairment of\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R signaling in\n MAGL<\/jats:styled-content>\n \u2212\/\u2212 mice was also accompanied by enhanced excitatory drive in the basolateral amygdala (\n BLA<\/jats:styled-content>\n )\u2010\n mPFC<\/jats:styled-content>\n circuit, with subsequent elevation of glutamate release to the\n mPFC<\/jats:styled-content>\n and anxiety\u2010like and obsessive\u2010compulsive behaviors, as assessed by the light\/dark box and marble burying tests, respectively. Collectively, these data provide evidence for a \u03b2\u2010arrestin2\u2010mediated desensitization of\n CB<\/jats:styled-content>\n 1<\/jats:sub>\n R in\n MAGL<\/jats:styled-content>\n \u2212\/\u2212 mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions.\n <\/jats:p>\n <\/jats:sec>\n \n \n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n In this study, the authors provide evidence that congenitally enhanced endocannabinoid levels in the neuronal circuits underlying anxiety\u2010like behavioral states (mainly medial prefrontal cortex, amygdala and hippocampus) lead to CB1R desenistization and anxiety and depression. MAGL\u2212\/\u2212 mice, a model of congenital overactivity of the eCB system, exhibited a compensatory impairment of CB1R signaling in anxiety\u2010associated brain areas and a subsequent change in excitatory\/inhibitory tone associated with altered score in the marble burying and light\/dark box test, in concomitance with anxiety and depression behavior states. These findings may have potential relevance to the understanding of the neurochemical effects of chronic CB1R overstimulation in cannabis abusers.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/jnc.13267","type":"journal-article","created":{"date-parts":[[2015,7,30]],"date-time":"2015-07-30T05:01:08Z","timestamp":1438232468000},"page":"799-813","source":"Crossref","is-referenced-by-count":91,"title":["Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor\n CB<\/scp>\n 1<\/sub>\n R signaling and anxiety\u2010like behavior"],"prefix":"10.1111","volume":"135","author":[{"given":"Roberta","family":"Imperatore","sequence":"first","affiliation":[{"name":"Endocannabinoid Research Group Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Morello","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Pozzuoli Italy"},{"name":"Department of Neurological and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Luongo","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Department of Experimental Medicine Division of Pharmacology \u201cL. Donatelli\u201d Second University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Taschler","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences University of Graz Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria","family":"Romano","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Department of Experimental Medicine Division of Pharmacology \u201cL. Donatelli\u201d Second University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilo","family":"De Gregorio","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Department of Experimental Medicine Division of Pharmacology \u201cL. Donatelli\u201d Second University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Belardo","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Department of Experimental Medicine Division of Pharmacology \u201cL. Donatelli\u201d Second University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabatino","family":"Maione","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Department of Experimental Medicine Division of Pharmacology \u201cL. Donatelli\u201d Second University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Di Marzo","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigia","family":"Cristino","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,9,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.741908"},{"key":"e_1_2_7_3_1","first-page":"2","article-title":"Activation of type\u20101 cannabinoid receptor shifts the balance between excitation and inhibition towards excitation in layer II\/III pyramidal neurons of the rat prelimbic cortex","volume":"20","author":"Boon F. 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