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Effects of chronic cannabidiol on serotonin/glutamate cortical release and molecular signaling pathways in bulbectomised depressed mice

AutorLinge, Raquel ; Jiménez-Sánchez, Laura ; Campa, Leticia ; Pilar-Cuéllar, Fuencisla ; Valdizán, Elsa M. ; Castro, Elena ; Adell, Albert ; Pazos, Ángel
Fecha de publicación21-oct-2014
Citación27th ECNP Congress (2014)
ResumenIt is well accepted that cannabidiol (CBD) exerts anxiolytic effects in behavioural assays both in humans and animals. Besides, it has been recently proposed as a putative new antidepressant drug. It has exhibited antidepressant-like properties in previous studies in the bulbectomy model of depression (OBX), presenting efficacy in the reversal of the anhedonia, as well as the hyperactivity in the open field [1]. However, the mechanism of action of this drug it has been extensively discussed and it remains unclear. On the one hand, the blockade of 5-HT1A receptors seems to be sufficient to avoid the acute anxiolytic effects of cannabidiol in the majority of the tests assayed. On the other hand, the CB1 receptor blockade also prevents some neurogenetic and behavioral consequences of the treatment. However, another receptors and pathways have been implicated in CBD [2], pointing to a probable complex mechanism involving a crosstalk among different systems. The aim of this study was to investigate the consequences of CBD chronic treatment in neurotransmitters release and in molecular signaling pathways, in order to better understand the underlying mechanism of the antidepressant actions observed in the OBX model. Methods: C57BL6 mice were bulbetomized or sham-operated and treated daily with cannabidiol or vehicle intraperitoneally for 2 weeks. Microdyalisis studies were performed in infralimbic medial prefrontal cortex (IL-mPFCx) and neurotransmitters were determined with HPLC coupled to electrochemical (5-HT) and fluorimetric (Glu) detection. Intracellular biomarkers were studied by western blotting of homogenized cell lysate and in situ hybridization of BDNF and TrkB. Results: In vivo mycrodyalisis in IL-mPFCx revealed that CBD administered chronically triggered increases in serotonin content both in sham (p<0.05) and in OBX mice (p<0.05). A concomitant elevation of the glutamate levels was observed but, interestingly, this effect was only present in the OBX group (p<0.05). The study of neuroplasticity biomarkers associated to antidepressant actions by Western Blot revealed some noticeable alterations in the OBX model. However, only the pmTOR/mTOR increase (p<0.05) and the BDNF elevation (p<0.01) were restored by the treatment with CBD. The in situ hibridation of the BDNF RNAm revealed a correlative increase in the BDNF expression in the medial prefrontal cortex (p<0.05) which was normalized after CBD chronic treatment, while no changes in the TrkB receptor expression were detected. Among the other brain areas analyzed, higher levels of BDNF (p<0.05) and TrkB (p<0.05) expression were measured in the piriform cortex. Conclusions: Chronic cannabidiol modulates the release of serotonin in mPFCx in all mice studied and interestingly, it also increased the glutamate release in OBX animals. The mechanism by which this compound produces the behavioural antidepressant effects might implicate acting upon serotonin and glutamate systems. Regarding intracellular biomarkers, it is noteworthy that the alterations found in some protein levels and expression in mPFCx of the OBX mice, such as BDNF or pmTOR/mTOR, were reversed by the CBD treatment. Taking together, we can infer that after the CBD treatment, a normalization of the unbalanced protein homeostasis of the bulbectomized animals is occurring.
DescripciónResumen del póster presentado en el 27th ECNP Congress (European College of Neuropsychopharmacology), celebrado del 18 al 21 de octubre de 2014 en Berlín (Alemania). Abstract publicado en: European Neuropsychopharmacology 24(Suppl. 2): S450 (2014). ISSN: 0924-977X. e-ISSN: 1873-7862. DOI: 10.1016/S0924-977X(14)70720-5
Aparece en las colecciones: (IIBB) Comunicaciones congresos
(IBBTEC) Comunicaciones congresos
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