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Abstract: Several techniques exist to study the rate of glucose uptake and metabolism in the brain but most of them are not sufficiently robust to permit extensive pharmacological analysis. Here we optimized an in vitro measurement of the simultaneous accumulation of the metabolizable and non-metabolizable 3H and 14C d-glucose analogues; permitting convenient large-scale studies on glucose uptake and metabolism in brain slices. Next, we performed an extensive pharmacological characterization on the putative glucoregulator role of the endocannabinoid system in the hippocampal slices of the rat, and the wild-type and the CB1 cannabinoid receptor (CB1R) knockout mice. We observed that 3H-3-O-methylglucose is a poor substrate to measure glucose uptake in the hippocampus. 3H-2-deoxyglucose is a better substrate but its uptake is still lower than that of 14C-U-d-glucose, from which the slices constantly metabolize and dissipate 14C atoms. Thus, uptake and the metabolism values are not to be used as standalones but as differences between a control and a treatment. The CB1R knockout mice exhibited ∼10% less glucose uptake and glucose carbon atom dissipation in comparison with the wild-type mice. This may represent congenital defects as acute treatments of the rat and mouse slices with cannabinoid agonists, antagonists and inhibitors of endocannabinoid uptake/metabolism failed to induce robust changes in either the uptake or the metabolism of glucose. In summary, we report here an optimized technique ideal to complement other metabolic approaches of high spatiotemporal resolution. This technique allowed us concluding that CB1Rs are at least indirectly involved in hippocampal glucoregulation. [Copyright &y& Elsevier]

Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB 1 receptor (CB 1 R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB 1 R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB 1 R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB 1 R agonists, WIN55212-2 (500 nM) and the CB 1 R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB 1 R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB 1 Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKβ levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB 1 R density within a month after T1D induction resolves previous controversial reports on forebrain CB 1 R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funding agencies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2020 Elsevier Inc. All rights reserved.)