Characterization of endogenous serotonin-mediated regulation of dopamine release in the rat prefrontal cortex

Endogenous serotonin (5-hydroxytryptamine, 5-HT)-mediated regulation of dopamine release in the rat prefrontal cortex was pharmacologically characterized using in vivo microdialysis. To increase synaptic 5-HT availability, a selective 5-HT uptake inhibitor fluoxetine was applied via the dialysis probe. Local perfusion of fluoxetine (30 and 100 μM) increased dopamine levels in a concentration-dependent manner. The fluoxetine (100 μM)-induced increases in dopamine release were abolished by pretreatment with the 5-HT 1B/1D receptor antagonist GR 127935 ( N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide] ) (10 and 100 μM). The facilitation of dopamine release was also prevented by selective inactivation of the mRNA encoding 5-HT 6 receptors using antisense oligonucleotides techniques. These findings suggest that not only 5-HT 1B receptors but also 5-HT 6 receptors are associated with the endogenous 5-HT-mediated facilitation of dopamine release. In other words, 5-HT 6 receptors may play, in part, a significant role in the functional interaction between the dopaminergic and serotonergic neuronal system in the rat prefrontal cortex.