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Transient gain of function of cannabinoid CB₁ receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes.

ABSTRACT: Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB₁ receptor (CB₁R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB₁R 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 CB₁R 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 CB₁R agonists, WIN55212-2 (500 nM) and the CB₁R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB₁R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB₁Rs 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 CB₁R density within a month after T1D induction resolves previous controversial reports on forebrain CB₁R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.

SUBMITTER: Pedro JR

PROVIDER: S-EPMC8281444 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes.

Pedro Joana Reis JR Moura Liane I F LIF Valério-Fernandes Ângela Â Baptista Filipa I FI Gaspar Joana M JM Pinheiro Bárbara S BS Lemos Cristina C Kaufmann Fernanda Neutzling FN Morgado Carla C Silva-Santos Carla S da CSD Tavares Isaura I Ferreira Samira G SG Carvalho Eugénia E Ambrósio António F AF Cunha Rodrigo A RA Duarte João M N JMN Köfalvi Attila A

Brain research bulletin 20200516

Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R 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 CB1R protein density was biphas ...[more]

PMID: 32428627

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Project description:The endocannabinoid system is a key regulator of the response to psychological stress. Inhibitors of monoacylglycerol lipase (MGL), the enzyme that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), exert anxiolytic-like effects in rodent models via 2-AG-dependent activation of CB1 cannabinoid receptors. In the present study, we examined whether the MGL inhibitor JZL184 might modulate persistent predator-induced fear in rats, a model that captures features of human post-traumatic stress disorder. Exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile chemical that is innately aversive to some rodent species, produced in male rats a long-lasting anxiety-like state that was measured 7 days later in the elevated plus maze test. Systemic administration of JZL184 [4, 8 and 16 mg/kg, intraperitoneal (IP)] 4 h before testing caused dose-dependent inhibition of MGL activity and elevation of 2-AG content in brain tissue. Concomitantly, the inhibitor suppressed TMT-induced fear behaviors with a median effective dose (ED50) of 4 mg/kg. A similar behavioral response was observed with another MGL inhibitor, KML29 (4 and 16 mg/kg, IP). Surprisingly, the effect of JZL184 was prevented by co-administration of the CB2 inverse agonist AM630 (5 mg/kg, IP), but not the CB1 inverse agonist rimonabant (1 mg/kg, IP). Supporting mediation of the response by CB2 receptors, the CB2 agonist JWH133 (0.3, 1 and 3 mg/kg, IP) also produced anxiolytic-like effects in TMT-stressed rats, which were suppressed by AM630. Notably, (i) JWH133 was behaviorally ineffective in animals that had no prior experience with TMT; and (ii) CB2 mRNA levels in rat prefrontal cortex were elevated 7 days after exposure to the aversive odorant. The results suggest that JZL184 attenuates the behavioral consequences of predator stress through a mechanism that requires 2-AG-mediated activation of CB2 receptors, whose transcription may be induced by the stress itself.

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Transient gain of function of cannabinoid CB₁ receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes.

Publications

Transient gain of function of cannabinoid CB<sub>1</sub> receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes.

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