Long-term fluoxetine treatment modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat prefrontal cortex through 5-hydroxytryptamine 1A receptor-dependent mechanisms.

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 (CB(1)) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB(1) 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-[(35)S]thio) triphosphate ([(35)S]GTP gamma S) in either area. Analysis of [(35)S]GTP gamma S-labeled G alpha subunits allowed for the detection of up-regulated CB(1) receptor coupling to G alpha(i2), G alpha(i3) in the PFC, and reduced coupling to G alpha(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 CB(1) receptor coupling to G alpha subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB(1) receptor signaling at the G alpha(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 Delta(9)-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 CB(1) receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.