In vivo microdialysis assessment of extracellular serotonin and dopamine levels in awake monkeys during sustained fluoxetine administration

Fluoxetine (FLU) rapidly enhances extracellular (EC) serotonin (5‐HT) in rodent brain, whereas the antidepressant effects of this drug in humans are typically not observed for 2–3 weeks. Thus, the effects of chronic oral FLU administration on neocortical and hippocampal EC 5‐HT, and on caudate EC 5‐HT and dopamine (DA), were examined in awake monkeys (Macaca fascicularis) using in vivo microdialysis (10.0 mg/kg; 3, 7, 14, and 21 days). On day 3, 5‐HT was significantly increased above baseline levels in hippocampus (HC) and caudate. There was a trend for an increase in neocortex EC 5‐HT levels. However, by day 7 5‐HT remained significantly elevated only in HC, although 5‐HT levels elsewhere had not completely returned to baseline. In contrast, levels of the 5‐HT metabolite, 5‐HIAA, were significantly reduced in all brain regions at all time points. Caudate DA levels tended to be decreased throughout FLU treatment. Local FLU and K+ infusion were also used at various times during chronic systemic FLU administration to evaluate changes in functional synaptic regulation. In general, these results, along with the significant decrease in 5‐HIAA levels and the tendency for basal EC 5‐HT levels to remain modestly elevated only in HC during sustained FLU administration, suggest a reduction in releasable pools of 5‐HT. Taken together with the trend for a decrease in caudate EC DA levels, these results do not appear to support the current hypothesis regarding the mechanism of action of SSRI antidepressants—that monoaminergic neurotransmission is progressively augmented during chronic treatment. Synapse 38:460–470, 2000. © 2000 Wiley‐Liss, Inc.

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