Either blocking or activating 5HT6 receptors (5-HT6R), respectively with antagonists or agonists, exert beneficial cognitive effects. Through phMRI, we demonstrated for the first time the similarities and discrepancies in the brain activation induced by an agonist and an antagonist of 5-HT6R. Both drugs similarly activate cortices and hippocampus. SB-271046 positively activates a network including the medio-dorsal raphe while EMD-386088 activates the rostral dorsal raphe. The different patterns of activation elicited in brain regions such as the habenula and the MG/DG nuclei (for SB-271046), or the amygdala and substantia nigra (for EMD-386088) supports different interactions with polysynaptic pathways.