Selective serotonin (5-HT) reuptake inhibitors (SSRIs) such as fluoxetine are among the most widely prescribed antidepressant drugs (ADs). On the other hand, recent data indicate that brain endocannabinoid (EC) system plays a role in the regulation of emotional behaviour. We have previously reported that chronic treatment with the fluoxetine significantly enhances the cannabinoid CB1 receptor functionality at the adenylyl cyclase (AC) level, without affecting receptor density. In the current study we have determined the involvement of serotonergic 5-HT1A receptor-dependent activity on the effects of chronic in vivo exposure to fluoxetine on the CB1 receptor density, coupling ability to Gi/o proteins and modulation of AC, in the rat prefrontal cortex. Animals were treated for 14 days with fluoxetine (10 mg/kg. day), fluoxetine plus the serotonin 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg. day), WAY100635 alone or vehicle. As previously found, CB1 receptor density, determined by saturation binding assays with the cannabinoid ligand [3H]CP55, 940, was not altered by chronic fluoxetine. The maximal effect of the cannabinoid agonist WIN55, 212-2 to stimulate [35S]GTPgammaS binding was found to be unchanged after any of the drug treatments assayed. In contrast, the enhancement in the maximal ability of WIN55, 212-2 to inhibit AC induced by fluoxetine (41.8% +/-3.7 of max. inhibition vs 30.0%+/-3.0, p< 0.05) was absent in rats exposed to fluoxetine plus WAY100635 (25.5%+/-3, 2), whereas chronic WAY100635 by itself did not modify any of these parameters (25.3%+/- 3.5). Taking into accounnt the reported existence of crosstalk mechanisms between brain EC and 5-HT systems, our results suggest that 5-HT neurotransmission, via 5-HT1A receptors, is mediating the CB1-linked transductional adaptations elicited by chronic ADs.

Trabajo presentado al 6th Forum of Federation of European Neuroscience Societies celebrado en Suiza del 12 al 16 de julio de 2008.

Ministy of Health (PND); MEC SAF07/61862; Instituto de Salud Carlos III, Mental Health CIBER.

Peer Reviewed