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.
Smith
T D
TD
Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Kuczenski
R
R
George-Friedman
K
K
Malley
J D
JD
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D017551:Microdialysis; D011188:Potassium / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D004298:Dopamine; D005473:Fluoxetine; D011188:Potassium; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors