Binge drinking (BD) is a common pattern of ethanol (EtOH) consumption by adolescents. The brain effects of the acute EtOH exposure are well-studied; however, the long-lasting cognitive and neurobehavioral consequences of BD during adolescence are only beginning to be elucidated. Environmental enrichment (EE) has long been known for its benefits on the brain and may serve as a potential supportive therapy following EtOH exposure. In this study, we hypothesized that EE may have potential benefits on the cognitive deficits associated with BD EtOH consumption. Four-week-old C57BL/6J male mice were exposed to EtOH following an intermittent 4-day drinking-in-the-dark procedure for 4 weeks. Then they were exposed to EE during EtOH withdrawal for 2 weeks followed by a behavioral battery of tests including novel object recognition, novel location, object-in-place, rotarod, beam walking balance, tail suspension, light-dark box and open field that were run during early adulthood. Young adult mice exposed to EE significantly recovered recognition, spatial and associative memory as well as motor coordination skills and balance that were significantly impaired after adolescent EtOH drinking with respect to controls. No significant permanent anxiety or depressive-like behaviors were observed. Taken together, an EE exerts positive effects on the long-term negative cognitive deficits as a result of EtOH consumption during adolescence.

The distribution and roles of the cannabinoid CB2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB2 receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer’s disease. By using a novel mouse model (CB2EGFP/f/f), we studied the distribution of cannabinoid CB2 receptors in the 5xFAD mouse model of Alzheimer’s disease (by generating 5xFAD/CB2EGFP/f/f mice) and explored the roles of CB2 receptors in microglial function. We used a novel selective and brain penetrant CB2 receptor agonist (RO6866945) as well as mice lacking the CB2 receptor (5xFAD/CB2−/−) for these studies. We found that CB2 receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB2 receptors as potential targets for the development of amyloid-modulating therapies.

Endokannabinoide-sistema (EKS) zelulen arteko komunikazio-sistema fisiologiko neuromodulatzaile garrantzitsuenetako bat da, eta helduaroan beraren funtzio ezagunena neurotransmisoreen doikuntza da. Azken urteotako ikerketek, aldiz, funtzio garrantzitsu horrez gain, garapen-prozesuetan ere parte-hartze handia duela erakutsi dute. Izan ere, zenbait artikuluk burmuinaren arauzko enbrioi-garapenerako EKSren beharra agerian utzi dute. Enbrioi-aroko ikerketek muga metodologiko handiak dituzte, eta orain arteko ikerketa gehienak hazkuntza zelularretan egin dira. Halere, burmuineko garuntxoaren kortexean, EKSren adierazpena handia da, eta jaio osteko garapen-prozesu guztiak biltzen ditu: pikor-zelulen morfogenesia, hain zuzen ere. Lan honetan, ultraegitura mailan, EKSren zenbait osagairen kokapena aztertu da; pikor-neuronen garapenaren faseetan baita helduaroan ere. CB1 kannabinoideen hartzailea, eta 2-arakidonil-glizerol (2-AG) endokannabinoidea sintetizatzen eta degradatzen dituzten entzimak —diazilglizerol lipasa (DAGL-α) eta monoazilglizerol lipasa (MAGL), hurrenez hurren— batera ageri dira hazkuntza- eta migrazio-prozesuetan dauden zuntz paraleloen axoietan jaio osteko garapen goiztiarrean. Konkretuki, CB1 eta DAGL-α zuntz paraleloen mintzean kokatzen dira, eta MAGL, mintzean ez ezik, zitoplasman ere adierazten da. Jaio osteko 12. egunean, zuntz paraleloek Purkinje neuronen arantza dendritikoekin kontaktu sinaptikoak ezartzen dituztenean, CB1 eta MAGL zuntz horien bukaera sinaptikoan mantenduko dira. CB1 bukaera sinaptiko horien mintzean kokatzen da, eta MAGL, aldiz, mintzaren hurrentasunean ez ezik, zitoplasman ere adierazten da. DAGL-α, zuntz paraleloen bukaera sinaptikotik desagertuko da, eta alde postsinaptikoan adieraziko da —hots, Purkinje neuronen arantza den- dritikoetan—. EKSn aztertutako 3 osagai horiek batera ageri dira zuntz paraleloetan garapenean zehar, kontaktu sinaptikoak ezarri arte. Horrela, zuntz horiek helduaren ezaugarriak lortzen dituztenean, hartzailea eta degradazio-entzima zuntz paraleloen bukaera sinaptikoan mantenduko dira. Sintesi-entzima, aldiz, axoi-profil horietatik desagertuko da, eta elementu postsinaptikoan adierazten hasiko da —hots, Purkinje neuronen arantza dendritikoetan—. Modu horretan, aztertutako aldi bakoitzean, EKSko osagaien kokapen espezifikoa bistaratu zen. Lortutako emaitzek EKS moldakorra dela eta funtzio desberdinetara egoki daitekeela iradokitzen dute, bere jarduna modu desberdinetan betez. Testuinguru horretan, garuntxoaren garapenean EKSren osagaien kokapen zehatza eta izaera identifikatzea alderdi kritikoa da, haurdun dauden emakumeen eta baita nerabeen kalamu-kontsumoak garunean egitura, funtzio eta portaera mailan eragiten dituen aldaketak ulertzeko. Horrez gain, jakintza hori terapeutikoki erabil daiteke, endokannabinoideen manipulazioak aplikazio klinikoak izan baititzake jaio osteko garapenean eta haurtzaroan gertatzen diren nerbio-sistemako gaixotasunen tratamenduan.

The alteration of the endocannabinoid tone usually associates with changes in the expression and/or function of the cannabinoid CB 1 receptor. In Alzheimer's disease (AD), amyloid beta (Aβ)-containing aggregates induce a chronic inflammatory response leading to reactivity of both microglia and astrocytes. However, how this glial response impacts on the glial CB 1 receptor expression in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques and concomitant subcellular changes in microglia and astrocytes, is unknown.The CB 1 receptor localization in both glial cells was investigated in the subiculum of male 5xFAD/CB 2 EGFP/f/f (AD model) and CB 2 EGFP/f/f mice by immuno-electron microscopy. The findings revealed that glial CB 1 receptors suffer remarkable changes in the AD mouse. Thus, CB 1 receptor expression increases in reactive microglia in 5xFAD/CB 2 EGFP/f/f , but remains constant in astrocytes with CB 1 receptor labeling rising proportionally to the perimeter of the reactive astrocytes. Not least, the CB 1 receptor localization in microglial processes in the subiculum of controls and closely surrounding amyloid plaques and dystrophic neurites of the AD model, supports previous suggestions of the presence of the CB 1 receptor in microglia. These findings on the correlation between glial reactivity and the CB 1 receptor expression in microglial cells and astrocytes, contribute to the understanding of the role of the endocannabinoid system in the pathophysiology of Alzheimer's disease.