The time course of fluoxetine-induced supersensitivity of hypothalamic 5-HT 2 A / 2 C receptors was examined. Daily injections of fluoxetine (7 or 14 days) significantly increased agonist ([ 1 2 5 I]DOI)-labeled high-affinity-state 5-HT 2 A / 2 C receptors in the hypothalamus, but not frontal cortex. No change was observed in the density of [ 3 H]ketanserin-labeled 5-HT 2 A receptors in either brain region. The levels of G q - and G 1 1 - proteins in the hypothalamus and cortex were not altered by fluoxetine. These results suggest that fluoxetine gradually increases the G-protein coupling of 5-HT 2 A / 2 C receptors without altering the levels of G q - or G 1 1 -proteins.