Evaluation of CB1 receptor knockout mice in the Morris water maze.

ABSTRACT The endocannabinoid system has been proposed to modulate a variety of physiological processes, including those that underlie cognition. The present study tested whether this system is tonically active in learning and memory by comparing CB 1 receptor knockout mice (CB 1 Ϫ/Ϫ ) to wild-type mice (CB 1 ϩ/ϩ ) in several Morris water maze tasks. Also, the effects of three cannabinoid agonists, (WIN 55,, and methanandamide, were evaluated in a working memory procedure. Both genotypes exhibited identical acquisition rates in a fixed platform procedure; however, the CB 1 Ϫ/Ϫ mice demonstrated significant deficits in a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. This phenotype difference was most likely due to an increased perseverance of the CB 1 Ϫ/Ϫ mice in that they continued to return to the original platform location, despite being repeatedly shown the new platform location. In addition, ⌬ 9 -THC (ED 50 ϭ 1.3 mg/ kg), WIN 55,212-2 (ED 50 ϭ 0.35 mg/kg), and methanandamide (ED 50 ϭ 3.2 mg/kg) disrupted the performance of CB 1 ϩ/ϩ mice in the working memory task at doses that did not elicit motivational or sensorimotor impairment as assessed in a cued version of the task. Furthermore, doses of each drug that were maximally disruptive in CB 1 ϩ/ϩ mice were ineffective in either N-(pip- ϩ/ϩ or CB 1 Ϫ/Ϫ mice. These results provide strong evidence that cannabinoids disrupt working memory through a CB 1 receptor mechanism of action, and suggest that the endocannabinoid system may have a role in facilitating extinction and/or forgetting processes

Comportamento de dois genótipos de milho cultivados em sistema de aléias preestabelecido com diferentes leguminosas arbóreas.

O cultivo em aléias tem sido recomendado como alternativa para a substituição da agricultura de corte e queima, no trópico úmido, devido à grande capacidade de produção de matéria orgânica e de reciclagem de nutrientes, mas algumas dúvidas quanto à sustentabilidade e à competição interespecífica são persistentes. O objetivo no trabalho foi avaliar a viabilidade da cultura do milho em um sistema de cultivo em aléias de leguminosas arbóreas. O delineamento experimental utilizado foi em blocos casualisados, com quatro repetições dos tratamentos: aléias de sombreiro (Clitoria fairchildiana), ingá (Inga edulis), guandu (Cajanus cajan) e leucena (Leucaena leucocephala) e uma testemunha sem aléias. Foram avaliadas a remobilização de carbono e nitrogênio, massa de grãos, massa de mil grãos e competição interespecífica entre as cultivares de milho e as leguminosas. A produção de grãos foi maior nas parcelas com C. fairchildiana e L. leucocephala. A produtividade do híbrido de milho foi superior à da variedade em todos os tratamentos. A produtividade e a massa de mil grãos de milho não são negativamente afetadas pela distância da linha da leguminosa arbórea. Esse estudo conclui que o sistema de aléias com leguminosas arbóreas é uma alternativa importante ao manejo sustentável dos agroecossistemas no tropico úmido. Além disso, nessa região a produtividade em grãos na cultura do milho é favorecida no sistema de aléias preeestabelecidas com as leguminosas arbóreas sombreiro, ingá e leucena e pela utilização de genótipos eficientes no aproveitamento do nitrogênio, cujo sincronismo entre a liberação e a absorção do N aplicado por meio das leguminosas deve ser aprimorado

Untangling the relationship between diet and visceral fat mass through blood metabolomics and gut microbiome profiling

BACKGROUND/OBJECTIVES: Higher visceral fat mass (VFM) is associated with an increased risk for developing cardio-metabolic diseases. The mechanisms by which an unhealthy diet pattern may influence VF development has yet to be examined through cutting-edge multi-omic methods. Therefore, our objective was to examine the dietary influences on VFM and identify gut microbiome and metabolite profiles that link food intakes to VFM. SUBJECTS/METHODS: In 2218 twins with VFM, food intake and metabolomics data available we identified food intakes most strongly associated with VFM in 50% of the sample, then constructed and tested the ‘VFM diet score’ in the remainder of the sample. Using linear regression (adjusted for covariates, including BMI and total fat mass) we investigated associations between the VFM diet score, the blood metabolomics profile and the faecal microbiome (n=889), and confirmed these associations with VFM. We replicated top findings in monozygotic (MZ) twins discordant (greater than or equal to1 s.d. apart) for VFM, matched for age, sex and the baseline genetic sequence. RESULTS: Four metabolites were associated with the VFM diet score and VFM: hippurate, alpha-hydroxyisovalerate, bilirubin (Z,Z) and butyrylcarnitine. We replicated associations between VFM and the diet score (Beta[s.e.]: 0.281[0.091]; P=0.002), butyrylcarnitine (0.199[0.087]; P=0.023) and hippurate (−0.297[0.095]; P=0.002) in VFM-discordant MZ twins. We identified a single species, Eubacterium dolichum to be associated with the VFM diet score (0.042[0.011], P=8.47 × 10−5), VFM (0.057[0.019], P=2.73 × 10−3) and hippurate (−0.075[0.032], P=0.021). Moreover, higher blood hippurate was associated with elevated adipose tissue expression neuroglobin, with roles in cellular oxygen homeostasis (0.016[0.004], P=9.82 × 10−6). CONCLUSION: We linked a dietary VFM score and VFM to Eubacterium dolichum and four metabolites in the blood. In particular, the relationship between hippurate, a metabolite derived from microbial metabolism of dietary polyphenols, and reduced VFM, the microbiome and increased adipose tissue expression of neuroglobin provides potential mechanistic insight into the influence of diet on VFM

Enhanced Brain Disposition and Effects of Δ9-Tetrahydrocannabinol in P-Glycoprotein and Breast Cancer Resistance Protein Knockout Mice

The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ9-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (−/−), Abcg2 (−/−) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (−/−) and Abcg2 (−/−) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (−/−) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis

Modulation of the endocannabinoids N-Arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) on Executive Functions in Humans

Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = −.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = −.17) or AEA (r = −.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches

Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity

Although oligomeric β-amyloid (Aβ) has been suggested to have an important role in Alzheimer disease (AD), the mechanism(s) of how Aβ induces neuronal cell death has not been fully identified. The balance of pro- and anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2 and Bcl-w versus Bad, Bim and Bax) has been known to have a role in neuronal cell death and, importantly, expression levels of these proteins are reportedly altered in the vulnerable neurons in AD. However, the roles of apoptotic proteins in oligomeric Aβ-induced cell death remain unclear in vivo or in more physiologically relevant models. In addition, no study to date has examined whether Bax is required for the toxicity of oligomeric Aβ. Here, we found that treatment with oligomeric Aβ increased Bim levels but decreased Bcl-2 levels, leading to the activation of Bax and neuronal cell death in hippocampal slice culture and in vivo. Furthermore, the inhibition of Bax activity either by Bax-inhibiting peptide or bax gene knockout significantly prevented oligomeric Aβ-induced neuronal cell death. These findings are first to demonstrate that Bax has an essential role in oligomeric Aβ-induced neuronal cell death, and that the targeting of Bax may be a therapeutic approach for AD