Abstract

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 type 1 (CB₁) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB₁ receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5′-O-(3-[³⁵S]thio) triphosphate ([³⁵S]GTPγS) in either area. Analysis of [³⁵S]GTPγS-labeled Gα subunits allowed for the detection of up-regulated CB₁ receptor coupling to Gα_i2, Gα_i3 in the PFC, and reduced coupling to Gα_i3 in the cerebellum of fluoxetine-treated rats. Concomitant administration of the 5-HT_1A receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (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 Gα_i-AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT_1A receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term Δ⁹-tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral 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.