2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for anandamide, is mediated by fatty acid amide hydrolase (FAAH) and, for 2-AG, is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, intimating a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL, JZL184, that, upon administration to mice, raises brain 2-AG by 8-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia, and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.

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Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer's disease (AD) remains largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, such as Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales. Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD.

The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB 1 cannabinoid receptors on neurons and CB 2 cannabinoid Correspondence should be addressed to N.S. (nstella@uw.edu). 11 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Neuroscience website. Competing Financial Interests:The authors declare no competing financial interests.Reprints and permissions information is available online at http://www.nature.com/reprintsandpermissions/. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2011 February 1. Published in final edited form as:Nat Neurosci. 2010 August ; 13(8): 951-957. doi:10.1038/nn.2601. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript receptors on microglia. Enzymes that hydrolyze 2-AG, such as monoacylglycerol lipase, regulate the accumulation and efficacy of 2-AG at cannabinoid receptors. We found that the recently described serine hydrolase α-β-hydrolase domain 6 (ABHD6) also controls the accumulation and efficacy of 2-AG at cannabinoid receptors. In cells from the BV-2 microglia cell line, ABHD6 knockdown reduced hydrolysis of 2-AG and increased the efficacy with which 2-AG can stimulate CB 2 -mediated cell migration. ABHD6 was expressed by neurons in primary culture and its inhibition led to activitydependent accumulation of 2-AG. In adult mouse cortex, ABHD6 was located postsynaptically and its selective inhibition allowed the induction of CB 1 -dependent long-term depression by otherwise subthreshold stimulation. Our results indicate that ABHD6 is a rate-limiting step of 2-AG signaling and is therefore a bona fide member of the endocannabinoid signaling system.In the nervous system, the endocannabinoids (eCBs) arachidonoylethanolamide (anandamide) and 2-AG are produced and inactivated by neurons and glia 1,2 . The production of eCBs increases in response to specific stimuli, including membrane receptor activation, ion channel opening and calcium influx 2 . eCBs are inactivated by cellular uptake followed by intracellular enzymatic hydrolysis 3,4 . The balance between this production and inactivation dictates the levels of extracellular eCB accumulation and the ensuing activation of CB 1 receptors expressed by neurons (regulating neurotransmitter release) and CB 2 receptors expressed by microglia (regulating their motility and ability to produce immunomodulators) [4][5][6][7] . Thus, the enzymatic steps that control the production and inactivation of eCBs constitute promising molecular targets for indirectly modulating CB 1 and CB 2 receptor activity, and thereby controlling neurotransmission and neuroinflammation.Of all the steps that control the accumulation of eCBs, the hydrolytic enzymes that inactivate anandamide and 2-AG represent the most promising pharmacological and genetic targets for fine-tuning the local accumulation of these lipid transmitters. Inhibition of fatty acid amide hydrolase (FAAH) increases...

An alternating copolymer, poly(2-(5-(5,6-bis(octyloxy)-4-(thiophen-2-yl)benzo[c][1,2,5]thiadiazol-7-yl)thiophen-2-yl)-9-octyl-9H-carbazole) (HXS-1), was designed, synthesized, and used as the donor material for high efficiency polymer solar cells. The close packing of the polymer chains in the solid state was confirmed by XRD. A J(sc) of 9.6 mA/cm(2), a V(oc) of 0.81 V, an FF of 0.69, and a PCE of 5.4% were achieved with HXS-1 and [6,6]-phenyl C(71)-butyric acid methyl ester (PC(71)BM) as a bulk heterojunction active layer spin-coated from a solvent mixture of 1,2-dichlorobenzene and 1,8-diodooctane (97.5:2.5) under air mass 1.5 global (AM 1.5 G) irradiation of 100 mW/cm(2).