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Effect of chronic Δ9-THC in combination with fluoxetine upon the functionality of endocannabionid system

Autor Castro, Elena ; Díaz, Álvaro ; Valdizán, Elsa M. ; Martín, Alicia ; Vidal, Rebeca ; Pazos, Ángel
Fecha de publicación 2009
EditorSociety for Neuroscience
Citación Neuroscience 2009
ResumenSeveral reports indicate that brain endocannabinoid (EC) system may be involved in depression and in antidepressant-like activity as demonstrated in some experimental models. In addition, recent data indicate that EC activity might be modulated by different antidepressant paradigms. To extend our knowledge on the crosstalk mechanisms between brain EC and serotonergic systems and their implication in depression, we have evaluated the effects of chronic in vivo exposure to the SSRI drug fluoxetine alone or in combination with Δ9- tetrahydrocannabinol (Δ9-THC) on the density and functionality of brain cannabinoid CB1 receptors as well as on the behavioural responses in depression/anxiety tests (open-field and elevated-plus maze). Animals (male Sprague-Dawley rats) were treated for 21 days with vehicle (saline), Δ9-THC (10 mg/kg/day, i.p.), fluoxetine (10 mg/kg/day, p.o.) and Δ9-THC plus fluoxetine. No significant changes were observed in the open-field and elevated-plus maze paradigms with any of the drug regimes. CB1 receptor density ([3H]CP55,940 saturation binding) was significantly decreased by chronic Δ9-THC (% reduction= 52.4 ± 7.3, p< 0.05; one-way ANOVA) and fluoxetine (% reduction= 42.4 ± 5.8, p< 0.05; one-way ANOVA) in the rat prefrontal cortex. However, these changes in the receptor density were similar to those observed by the concomitant administration of Δ9-THC plus fluoxetine. In addition, the maximal effect of the cannabinoid agonist WIN55,212-2 to stimulate [35S]GTPγS binding was attenuated by chronic Δ9-THC alone or in combination with fluoxetine; however chronic fluoxetine did not alter CB1 agonist-stimulated [35S]GTPγS binding. Finally, the maximal ability of WIN55,212-2 to inhibit AC (forskolin-stimulated-cAMP accumulation) was significantly enhanced (Emaxvehicle= 64.5 ± 8.3 vs Emaxfluoxetine= 48.5 ± 13.4; p < 0.01; one-way ANOVA) and decreased (ImaxΔ9-THC = 84.5 ± 7.4 %; p < 0.01 vs vehicle; one-way ANOVA) in the prefrontal cortex of rats treated with fluoxetine and Δ9-THC respectively. By contrast, in the Δ9-THC plus fluoxetine treated group the inhibition of AC induced by WIN55,212-2 was not significantly different from the vehicle group. Our data indicate that chronic stimulation of EC transmission desensitizes the receptorial and postreceptorial mechanisms coupled to CB receptors. They also suggest that the association of a CB1 agonist with SSRIs does not potentiate the changes in the functionality of CB receptors induced by antidepressant drugs.
Descripción Trabajo presentado al 39th annual meeting of Neuroscience celebrado en Chicago del 17 al 21 de octubre de 2009.
URI http://hdl.handle.net/10261/93388
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