Recent data indicate that brain endocannabinoid (EC) system plays a role in the regulation of emotional behaviour, and might be modulated by different antidepressant paradigms. Furthermore, different experimental data support the existence of crosstalk mechanisms between brain EC and 5-HT systems. In the current study we determined the effects of chronic in vivo exposure to the SSRI fluoxetine on the density and functionality of cannabinoid CB1 receptors, and the involvement of 5-HT1A receptors in those effects. Animals were treated for 14 days with vehicle, fluoxetine (10 mg/kg/day), fluoxetine plus the serotonin 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg/day) or WAY100635 alone. CB1 receptor density ([3H]CP55,940 saturation binding) and maximal effect of the cannabinoid agonist WIN55,212-2 to stimulate [35S]GTP¿S binding were not altered by chronic fluoxetine in the rat prefrontal cortex . In contrast, the maximal ability of WIN55,212-2 to inhibit AC (forskolin-stimulated-cAMP accumulation) was significantly (F = 6.11; p =0.004; one-way ANOVA) enhanced in the prefrontal cortex of rats treated with fluoxetine (Imax = 41.8 ± 3.7%) vs vehicle (Imax = 30.0 ± 3.0%), indicating that increased CB1 receptor functionality at the AC level is one of the long-term adaptations induced by this SSRI. This enhanced response of WIN55,212-2 was absent in rats exposed to chronic fluoxetine plus WAY100635 (Imax = 25.5 ± 3.2%) or WAY100635 alone (Imax = 25.3 ± 2.5%). This increase in cortical CB1 receptor functionality was not observed after a single dose of 10 mg/kg of fluoxetine (Imax = 29.3 ± 2.1%). Otherwise the ability of WIN55,212-2 to inhibit AC was not increased by chronic fluoxetine treatment (14 days) in cerebellum (Imax = 23.5 ± 1.0 %) a region in which 5HT1A receptors are not expressed. Our results suggest a role for 5-HT1A receptors in the mediation of CB1-linked transductional adaptations after chronic fluoxetine.

Trabajo presentado a la 9ª Reunión anual de la Sociedad Española de Investigación sobre Cannabinoides celebrada en Córdoba del 27 al 29 de noviembre de 2008.

Support: MICINN (SAF07/61862), Plan Nacional sobre Drogas, Fundación Mutua Madrileña

Peer Reviewed