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Effect of chronic Δ9-THC alone and in combination with fluoxetine on CB1 receptor-dependent signalling pathways in OB rats

AuthorsVidal, Rebeca CSIC ORCID; Romero-Presno, Beatriz CSIC; Martín, Alicia CSIC; Treceño, Begoña CSIC; Valdizán, Elsa M. CSIC ORCID; Díaz, Álvaro CSIC ORCID; Pazos, Ángel CSIC ORCID; Castro, Elena CSIC ORCID
Issue Date13-Nov-2010
Citation40th Annual Meeting Neuroscience (2010)
AbstractBrain endocannabinoid (EC) system has been involved in depression as well as in antidepressant-like activity. Several reports indicate that EC activity might be modulated by different antidepressant paradigms. In our study, we evaluated the effect of chronic (21 days) treatment with fluoxetine (10 mg/kg/day, p.o), Δ9-tetrahydrocannabinol (Δ9-THC, 10 mg/kg/day, i.p) or their combination on CB1 signalling pathway in an animal model of depression such as olfactory bulbectomy (OB). Olfactory bulbectomy resulted in a significant motor hyperactivity as measured by open field test, a behavioural modification reversed by chronic fluoxetine. OB-rats showed an increase of CB1 receptor density in rat prefrontal cortex compared to sham-operated rats, which was antagonized by chronic treatment with Δ9-THC alone and associated with fluoxetine. In the same way, Δ9-THC alone or in combination with the antidepressant induced a down-regulation of CB1 receptors in naïve rats. At the level of G-protein coupling, OB-rats exhibited showed an increase in the degree of stimulation of 35SGTPγS binding by the agonist WIN55,212-2 with respect to sham operated rats. This effect was reverted in Δ9-THC and Δ9-THC plus fluoxetine treated groups. In naïve rats, Δ9-THC alone or in combination with fluoxetine also decreased CB1-agonist induced stimulation of 35SGTPγS binding while chronic fluoxetine had no significant effect. Finally, the ability of WIN55,212-2 to inhibit the forskolin-stimulated-cAMP accumulation was significantly enhanced and decreased in the prefrontal cortex of rats treated with fluoxetine and Δ9-THC, respectively. These effects were observed in both naïve and OB rats; in contrast, the inhibition induced by WIN55,212-2 on cAMP accumulation in Δ9-THC plus fluoxetine rats was not significantly different from their respective vehicle groups. Our data suggest, firstly, that fluoxetine normalizes the behavioural modifications induced by olfactory bulbectomy, together with a clear, although non significant tendency to avoid the increase in the density of CB1 receptors. Secondly, the changes observed on the CB1 receptor-dependent signalling pathways in prefrontal cortex after chronic Δ9-THC are probably the compensatory consequence of a chronic stimulation of the receptor, rather than being related to the possible antidepressant effect of this compound.
DescriptionTrabajo presentado al: "40th Annual Meeting Neuroscience" celebrado en California (EE.UU.) del 13 al 17 de noviembre de 2010.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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