TY - JOUR T1 - CHRONIC FLUOXETINE MODULATES CB<sub>1</sub> RECEPTOR-MEDIATED INHIBITION OF ADENYLYL CYCLASE IN THE RAT PREFRONTAL CORTEX THROUGH 5-HT<sub>1A</sub> RECEPTOR-DEPENDENT MECHANISMS JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.060079 SP - mol.109.060079 AU - Susana Mato AU - Rebeca Vidal AU - Elena Castro AU - Alvaro Diaz AU - Angel Pazos AU - Elsa M Valdizan Y1 - 2009/12/07 UR - http://molpharm.aspetjournals.org/content/early/2009/12/07/mol.109.060079.abstract N2 - Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid CB1 receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Chronic fluoxetine (10 mg/kg.day) enhanced CB1 receptor inhibition of AC in the PFC and reduced it in the cerebellum, without altering receptor density and agonist-stimulation of [35S]GTPγS in either area. Analysis of [35S]GTPγS labeled Gα subunits allowed detection of upregulated CB1 receptor coupling to Gαi2, Gαi3 in the PFC and reduced coupling to Gαi3 in the cerebellum of fluoxetine-treated rats. Concomitant administration of the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg.day) reduced fluoxetine-induced modulation of CB1 receptor coupling to Gα subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB1 receptor signaling at the Gαi-AC transduction level is a long-term adaptation induced by fluoxetine in the PFC, and point to a role for 5-HT1A receptors in this effect. Basal AC activity, PKA catalytic subunit expression and pCREB/CREB ratio were also upregulated in the PFC of fluoxetine-treated animals, while no differences were detected in the cerebellum. Interestingly, chronic Δ9-THC did not elicit antidepressant-like effects neither modulated behavioural responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB1 receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.The American Society for Pharmacology and Experimental Therapeutics ER -